MYSELF

DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 36Yrs Exp. in the feld of Organic Chemistry,Working for AFRICURE PHARMA as ADVISOR earlier with GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64

DR ANTHONY MELVIN CRASTO Ph.D

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

Verified Services

View Full Profile →

When can a Chemical Substance be qualified as a “New Active Substance”? The New Reflection Paper of the EMA gives Information

February 4, 2016 3:29 am / Leave a comment

When can a Chemical Substance be qualified as a “New Active Substance”? The New Reflection Paper of the EMA gives Information

A chemical structure with a therapeutic moiety for which no authorisation dossier has been submitted so far and which is – from a chemical structure point of view – not related to any other authorised substances is per se a “NAS” (New Active Substance). But what about a physiologically active molecule present for example in different salts or esters? In which cases do the different derivatives of an effective substance have the NAS status?

The EMA provides clarification to these questions in a new Reflection Paper which was published on 19 January this year. The document entitled “Reflection paper on the chemical structure and properties criteria to be considered for the evaluation of new active substance (NAS) status of chemical substances” describes the criteria according to which isomers, mixtures of isomers, complexes, derivatives, esters, ethers, salts and other solid forms of physiologically active molecules can be classified as “NAS “. If an applicant claims the NAS status of a substance to the regulatory authority in the centralised (CP) or decentralised procedure (MRP/DCP), the authority will first check whether the claim is justified. Afterwards – in case of a positive decision – the usual review of the application dossier will be performed.

http://www.gmp-compliance.org/enews_5189_When-can-a-Chemical-Substance-be-qualified-as-a-%22New-Active-Substance%22-The-New-Reflection-Paper-of-the-EMA-gives-Information_n.html

The applicant can refer to the criteria described in this Reflection Paper to substantiate his/ her claim of a NAS status. In general, the evidence has to be brought for the derivative in question that it differs significantly in properties with regard to efficacy and /or safety from the already approved active substance.

The scope of this Reflection Papers covers neither biological and biotechnological active substances nor active substances to be included in radiopharmaceuticals.

//////

New Website ECA Validation Group: Version 02 of ECA´s Good Practice Guide on Validation online available

February 4, 2016 3:26 am / Leave a comment

The ECA Validation Group was founded in autumn 2011 by representatives of the pharmaceutical industry after ECA´s 4th European GMP Conference. The mission of the group is to assemble knowledge on Validation, for example by continuously developing ECA´s Process Validation Good Practice Guide. Now the Validation Group launched a new website.

Since the ECA Foundation was established back in 1999 its mission has been to provide support to the Pharmaceutical Industry and Regulators to promote the move towards a harmonised set of GMP and regulatory guidelines by providing information and interpretation of new or updated guidances. For that purpose the ECA has initiated and established various working and interest groups concentrating on different topics.

The ECA Validation Group was founded in autumn 2011 by representatives of the pharmaceutical industry after ECA´s 4th European GMP Conference. This group’s mission is to assemble knowledge on Validation, for example by continuously developing ECA´s Process Validation Good Practice Guide.

Now the group launched its new website to provide members and those interested with information and practical tools. Here’s what you can find on the new website:

Current News
A news archive
Training Courses and Validation Conferences
ECA´s Process Validation Good Practice Guide
Discussion Forum
Presentations
Useful links
Q&A section
Membership information

Members of the group have now the opportunity to download the version 2 of ECA´s Good Practice Guide on Validation free of charge. On 174 pages the revised Good Practice Guide comprises the main elements of the new validation approach (“what to do”). On the other hand, it also serves as a supporting guide for the implementation (“how to do”).

To find out more we invite you to visit the ECA´s Validation Group new website.

//////

Frequent Asked Question: Which Level of Ozone is Required in a Hot- or Cold-Stored WFI System?

February 4, 2016 3:22 am / Leave a comment

Ozone can be used for the sanitisation of water systems. Which level of concentration is required in water – i.e. in WFI – depends on different factors. Read more about the sanitisation of water systems with ozone.

http://www.gmp-compliance.org/enews_05131_Frequent-Asked-Question-Which-Level-of-Ozone-is-Required-in-a-Hot–or-Cold-Stored-WFI-System_15160,15154,15090,Z-PEM_n.html

The usage of ozone is only senseful in cold water systems. But the decisive question is whether ozone is used for a short-term (1-2 hours) or for a long term (> 6 hours) prevention of microbial growth. In the first case, > 50 ppb ozone is generally sufficient whereas in the second case at least 20 ppb are required.

One should keep in mind that WFI cold systems have basically a higher risk of microbial contamination. The need for ozone in large ring systems or in areas difficult to access may be higher. The ozone levels mentioned should thus be achieved in the return flow. Setting the correct ozone concentration for the system must be done within the scope of the PQ – i.e. validation of the water system.

In contrast, ozonisation of hot-stored WFI systems doesn’t make sense. Indeed, the half-life of ozone considerably decreases at temperatures over 40° Celsius. Moreover, the heat in hot WFI system causes sanitisation itself; the usage of additional ozone wouldn’t be meaningful. The risk of biofilm formation in hot-stored WFI systems is considerably lower.

/////

PF 04995274, a 5-HT4Partial Agonist

February 3, 2016 5:19 am / Leave a comment

PF-04995274,

(R)-4-((4-(((4-(Tetrahydrofuran-3-yloxy)-1,2-benzisoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol

4-(4-{4-[(R)-(Tetrahydro-furan-3-yl)oxy]-benzo[d]isoxazol-3-yloxymethyl}-piperidin-1-ylmethyl)-tetrahydro-pyran-4-ol

CAS 1331782-27-4
UNII: XI179PG9LV

MF C23-H32-N2-O6

MW 432.5138

a 5-HT4Partial Agonist

PHASE 1 Alzheimer’s type dementia.

Pfizer Inc. INNOVATOR

5-HT₄ agonists have attracted attention for therapeutic value in the treatment of Alzheimer’s Disease (AD) and cognitive impairment.Acting to increase levels of acetylcholine and soluble APP alpha, 5-HT₄ agonists have the potential to demonstrate both ameliorative and disease modifying effects

(R)-4-((4-((4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)methyl)piperidin-1-yl)methyl)tetrahydro-2/-/-pyran-4-ol and pharmaceutically acceptable salts thereof. This invention also is directed, in part, to a method for treating a 5-HT₄ mediated disorder in a mammal. Such disorders include acute neurological and psychiatric disorders, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, Alzheimer’s disease, Huntington’s Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug- induced Parkinson’s disease, muscular spasms and disorders associated with muscular spasticity including tremors, depression, epilepsy, convulsions, migraine, urinary incontinence, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, mood disorders, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, emesis, brain edema, pain, tardive dyskinesia, sleep disorders, attention deficit/hyperactivity disorder, attention deficit disorder, disorders that comprise as a symptom a deficiency in attention and/or cognition, and conduct disorder

^a(a) SOCl₂, DMAP, acetone, DME, RT, 81%;

(b) DEAD, PPh₃, THF, RT, 65%;

(d) K₂CO₃, water, MeOH, 50 °C, 76%;

(e) CDI, THF, 50 °C, 43%;

(f) DEAD, PPh₃, THF, reflux, 51%;

(g) HCl, Et₂O, RT, 81%;

(h) TEA, MeOH, reflux, 50%.

PAPER

Journal of Medicinal Chemistry (2012), 55(21), 9240-9254

http://pubs.acs.org/doi/abs/10.1021/jm300953p

The cognitive impairments observed in Alzheimer’s disease (AD) are in part a consequence of reduced acetylcholine (ACh) levels resulting from a loss of cholinergic neurons. Preclinically, serotonin 4 receptor (5-HT₄) agonists are reported to modulate cholinergic function and therefore may provide a new mechanistic approach for treating cognitive deficits associated with AD. Herein we communicate the design and synthesis of potent, selective, and brain penetrant 5-HT₄ agonists. The overall goal of the medicinal chemistry strategy was identification of structurally diverse clinical candidates with varying intrinsic activities. The exposure–response relationships between binding affinity, intrinsic activity, receptor occupancy, drug exposure, and pharmacodynamic activity in relevant preclinical models of AD were utilized as key selection criteria for advancing compounds. On the basis of their excellent balance of pharmacokinetic attributes and safety, two lead 5-HT₄ partial agonist candidates 2d and 3 were chosen for clinical development.

PATENT

https://www.google.co.in/patents/WO2011101774A1?cl=en

(R)-4-((4-((4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol , hereinafter referred to as “Compound X,” and having the following structure:

Compound X

Example 1 : Synthesis of iR)-4-ii4-i(4-itetrahvdrofuran-3-yloxy)benzord1isoxazol-3-yloxy)methyl)piperidin-1 -yl)methyl)tetrahvdro- 2 -pyran-4-ol

Methyl 2-fluoro-6-hydroxybenzoate (2): To a 20L jacketed reactor were charged 2-fluoro-6-hydroxybenzoic acid (Oakwood Products; 0.972 kg, 6.31 mol), methanol (7.60 L) and sulfuric acid (0.710 kg, 7.24 mol, 1 .15 eq). The jacket temperature was heated to 60°C and the reaction mixture was stirred for 45 h. The reaction mixture was concentrated under vacuum and approximately 7.5 L of methanol distillates were collected. The resulting thin oil was cooled to 20°C. Water (7.60 L) and ethyl acetate (7.60 L) were charged to the reactor, and the product extracted into the organic layer. The EtOAc solution was washed with a solution of sodium bicarbonate (1.52 Kg) in water (6.92 L) followed by a brine solution of sodium chloride (1.74 kg) in water (4.08 L). The resulting EtOAc solution was concentrated to dryness. A light orange oil was isolated; the oil slowly crystallized upon standing to give the title compound (2) (0.952 Kg, 5.60 mol, 89% yield). ¹ H NMR (400 MHz, CDCI₃) δ ppm 3.97 (s, 3H), 6.59 (ddd, J=10.9, 8.2,1 .2, 1 H), 6.76 (dt, J=8.2, 1 .1 , 1 H), 7.35 (td, J=8.6, 6.3, 1 H), 1 1.24 (s, 1 H); ¹³C NMR (400 MHz, CDCI₃) δ ppm 52.65, 102.56 (d, J=13), 106.90 (d, J=23), 1 13.31 (d, J=3.1 ), 135.34 (d, J=1 1 .5), 161 .02, 163.31 (d, J=62.2), 169.87 (d, 3.8); MS 171.045 (m+1 ). 2-Fluoro-N,6-dihydroxybenzamide (3): To a 50L reactor was charged water (4.47 L) and hydroxylamine sulfate (6.430 kg, 39.17 mol), the mixture was stirred at 25°C. A solution of potassium carbonate (3.87 Kg, 27.98 mol) in water (5.05 L) was slowly added to the reaction mixture to form a thick white mixture that was stirred at 20°C. A solution of methyl 2-fluoro-6-hydroxybenzoate (2) (0.952 Kg, 5.60 mol) in methanol (9.52 L) was slowly added to the reactor resulting in mild off gassing. The reaction mixture was then heated to 35°C and stirred for 20 h. The reaction mixture was cooled to 15°C and stirred for 1 h. The mixture was filtered to remove inorganic material. The reactor was rinsed with methanol (2.86 L) and the tank rinse was used to wash the inorganic cake.

Analysis of the cake indicated that it contained product. To a 20L reactor was charged methanol (10 L) and the inorganic cake and the mixture was stirred at 25°C for 30 min. The mixture was filtered and the cake washed with methanol (3 L).

The combined filtrates were charged back into the reactor and concentrated under vacuum with the jacket temperature set at 40°C until approximately 10 L remained. The mixture was held at 25°C and cone. HCI (5.51 L) was added. The reactor was cooled to 15°C and stirred for 2 h. The white slurry was filtered and the resulting product cake was washed with water (4.76L), blown dry with nitrogen and then dried in a vacuum oven at 40°C for 12 h. The desired product (3) (747 g, 4.36 mol), was isolated in 78% yield. ¹ H NMR (400 MHz, CD₃OD) δ ppm 4.91 (s, 3H), 6.63 (ddd, J=10.9, 8.5, 0.8, 1 H), 6.72 (dt, J=8.2, 0.8, 1 H), 7.31 (td, J=8.2, 6.6, 1 H); MS 172.040 (m+1 ).

4-Fluorobenzo[d]isoxazol-3-ol (4): To a 20L jacketed reactor were charged tetrahydrofuran (2.23 L) and 1 ,1 ‘-carbonyldiimidazole (0.910 Kg, 5.64 mol). The resulting mixture was stirred at 20°C. Then a solution of 2-fluoro-N,6-dihydroxybenzamide (3) (744 g, 4.34 mol) in tetrahydrofuran (4.45 L) was slowly charged to the reactor maintaining the temperature below 30°C and stirred at 25°C for 30 min during which some off gassing was observed. The reaction mixture was heated to 60°C over 30 min and stirred for 6 h. The reactor was cooled to 20°C followed by the addition of 1 N aqueous hydrogen chloride (7.48L) over 15 min to adjust the pH to 1. The jacket temperature was set to 35°C and the reaction mixture concentrated under vacuum to remove approximately 6.68L of THF. The reactor was cooled to 15°C and stirred for 1 h. The resulting white slurry was filtered, the cake was washed with water (3.71 L) and dried in a vacuum oven at 40°C for 12 h. The desired product, (4) (597 g, 3.90 mol), was isolated in 90% yield. ¹ H NMR (400 MHz, CD₃OD) δ ppm 4.93 (b, 1 H), 6.95 (dd, J=10.1 , 8.6, 1 H), (d, J=8.6, 1 H), 7.52-7.57 (m, 1 H); LRMS 154.029 (m+1 ).

Tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate (5): To a 20L jacketed reactor were charged dichloromethane (8 L), N-boc-4-piperdine methanol (0.982 Kg, 4.56 mol) and p-toluenesulfonyl chloride (0.970 Kg, 5.09 mol) and the resulting mixture was stirred at 20°C for 5 min. Triethylamine (0.94 Kg, 9.29 mol) was added to the reactor via an addition funnel and the resulting deep red solution was stirred at 25°C for 16 h. A solution of sodium carbonate (0.96 Kg, 9.06 mol) in water (7.04 L) was charged to the reaction mixture and stirred for 1 h at 20°C. The phases were split and the organic layer washed with brine (6 L) and concentrated at 40°C to a low stir volume. Dimethylacetamide (2 L) was charged to the reactor and concentration continued under full vacuum at 40°C for 1 h. The solution of tert-butyl 4-(tosyloxymethyl)piperidine-l -carboxylate (5) in dimethyl acetamide was held for further processing. Yield was assumed to be 100% with approximately

90% potency. A sample was pulled and concentrated to dryness for purity analysis. ¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .02-1 .12 (m, 2H), 1.14 (s, 9H), 1 .59-1.64 (m, 2H), 1.75-1.87 (m, 1 H), 2.43 (s, 3H), 2.55-2.75 (m, 2H), 3.83 (d, J=6.7, 2H), 3.95-4.20 (b, 2H), 7.33 (d, 8.6, 2H), 7.76 (d, 8.2, 2H); ¹³C NMR (400 MHz, CDCI₃) δ ppm 21 .64, 28.15, 28.39, 35.74, 73.97, 79.50, 126.99, 127.84, 129.86, 132.84, 144.84, 154.63; LRMS 739.329 (2m+1 ).

Tert-butyl 4-((4-fluorobenzo[d]isoxazol-3-yloxy)methyl)piperidine-1-carboxylate (6): To a 20L jacketed reactor were charged dimethylacetamide (4.28 L), tert-butyl 4-(tosyloxymethyl)piperidine-1 -carboxylate (5) (1.68 Kg, 4.56 mol), 4-fluorobenzo[d]isoxazol-3-ol (4) (540 g, 3.51 mol), and potassium carbonate (960 g, 6.98 mol) resulting in a thick beige slurry. The reaction mixture was heated to 50°C and stirred for 20 h and then cooled to 20°C, followed by the addition of water (7.5 L) and ethyl acetate (5.37 L). After mixing for 15 min, the phases were settled and split. The organic layer was washed with water (5.37 L), sending the aqueous wash to waste. The organic mixture was distilled under vacuum with a maximum jacket temperature of 40°C until approximately 5 L remained in the reactor. Methanol (2.68 L) was added and the resulting solution concentrated under vacuum to about 3 L of a yellow oil. Methanol (2.68 L) was charged to the reactor and the resulting solution was stirred at 25°C for 15 min. Water (0.54 L) was added over 15 min resulting in a white slurry. The mixture was cooled to 15°C, stirred for 1 h and then filtered. The filter cake was washed with a solution of water (0.54 L) in methanol (2.14 L), then air dried for 30 min, transferred to a vacuum oven and dried at 40°C for 12 h. The desired product, (6) (746 g, 2.13 mol), was isolated in 61 % yield. ¹ H NMR (400 MHz, CDCI₃) δ ppm 1.23-1 .37 (m, 2H), 1 .45 (s, 9H), 1 .78-1 .88 (m, 2H), 2.04-2.17 (m, 1 H), 2.67-2.83 (m, 2H), 4.02-4.26 (m, 2H), 4.28 (d, 6.6, 2H), 6.89 (dd, J=8.6, 7.5, 1 H), 7.21 (d, J=9, 1 H), (td, 8.6, 4.9); LRMS 351.171 (m+1 ).

(R)-Tert-butyl 4-((4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)methyl)piperidine-1-carboxylate (8): To a 20 L glass reactor with the jacket set to 20°C were charged (R)-tetrahydrofuran-3-ol (7) (297 g, 3.37 mol) and dimethylacetamide (5.1 L). 2.0 M sodium bis(trimethylsilyl)amide in THF (1.37 L, 2.74 mol) was slowly added via an addition funnel while maintaining a pot temperature less than 30°C. The resulting orange/red solution was stirred at 25°C for 30 min. Then, tert-butyl 4-((4-fluorobenzo[d]isoxazol-3-yloxy)methyl)piperidine-1 -carboxylate (6) (640.15 g, 1.83 mol) was charged and the reaction mixture was stirred at 25°C for 16 h. The reaction mixture was cooled to 20°C and water (6.4 L) was slowly added over 45 min maintaining a pot temperature of less than 35°C. Ethyl acetate (6 L) was added and the biphasic mixture was stirred for 15 min and then separated. The aqueous layer was back extracted with additional ethyl acetate (4 L). The combined organics were then washed with water (5 L) and a 20% brine solution (5 L). The organic mixture was concentrated under vacuum with the jacket temperature set to 40°C to approximately 3 L and held for further processing. Quantitative yield of the desired product, (8) (0.76 Kg, 1 .82 mol), in ethyl acetate was assumed. A sample was pulled and concentrated to dryness for purity analysis. ¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .25-1.38 (m, 2H), 1 .44 (s, 9H), 1.76-1 .84 (m, 2H), 1 .89-1.97 (b, 1 H), 1 .99-2.12 (m, 1 H), 2.14-2.28 (m, 2H), 2.63-2.84 (m, 2H), 3.90-4.21 (m, 6H), 4.24 (d, J=6.3, 2H), 5.00-5.05 (m, 1 H), 6.48 (d, J=8.2, 1 H), 6.98 (d, J=8.6, 1 H), 7.37 (t, J=8.2, 1 H); LRMS 419.216 (m+1 ).

(R)-3-(Piperidin-4-ylmethoxy)-4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazole 4-methylbenzenesulfonate (9): To a 20L jacketed reactor charged ethyl acetate (6.1 L), (R)-tert-butyl 4-((4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)methyl)piperidine-1 -carboxylate (8) (0.76 kg, 1 .82 mol) and p-toluenesulfonic acid monohydrate (0.413 kg, 2.17 mol) and stirred at 20°C for 30 min. The reactor jacket was heated from 20 to 65°C over

1 h and then held at 65°C for 16 h. The reactor was cooled to 15°C over 1 h and granulated for 2 h. The resulting slurry was filtered, the cake was washed with EtOAc (3 L) and then air dried on the filter for 30 min. The cake was transferred to a vacuum oven and dried at 40°C for 12 h. The desired product, (9) (854 g, 1.74 mol), was isolated in 96% yield (two steps). ¹ H NMR (400

MHz, CD₃OD) δ ppm 1.54-1 .67 (m, 2H), 2.04-2.18 (m, 3H), 2.19-2.36 (m, 2H), 2.33 (s, 3H), 3.01 -3.12 (m, 2H), 3.41-3.50 (m, 2H), 3.86-4.01 (m, 4H), 4.26 (d, J=6.3, 2H), 4.90 (s, 2H), 5.14-5.19 (m, 1 H), 6.72 (d, J=8.2, 1 H), 7.02 (d, J=8.6, 1 H), 7.21 (d, J=7.8, 2H), 7.48 (t, J=8.6, 1 H), 7.70 (d, J=8.2, 2H); LRMS 319.165 (m+1 ).

(R)-4-((4-((4-(Tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol (11): To a

20L jacketed reactor were charged water (7.5 L) and sodium carbonate (0.98 kg); the mixture was stirred at 20°C until all solids had dissolved. Then (R)-3-(piperidin-4-ylmethoxy)-4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazole 4-methylbenzenesulfonate (9) (750 g, 1 .53 mol) and ethyl acetate (6.0 L) were added to the reactor and stirred at 20°C for 30 min. The phases were split and the lower aqueous layer was back extracted twice with ethyl acetate (6.0 L and then 3.75 L). The organic layers were combined in the 20L reactor and washed twice with brine (3.0 L). The ethyl acetate solution was concentrated to under vacuum at 45°C to a low stir volume. Isopropyl alcohol (3.75 L) was added and concentration continued until 2 L remained in the reactor.

Additional isopropyl alcohol (2.75 L) was added and the mixture cooled to 25°C. To the reactor was charged 1 ,6-dioxaspiro[2.5]octane (10) (260 g, 2.29 mol) and the resulting solution heated to 50°C and stirred for 16 h. The reaction mixture was cooled to 30°C and water (15 L) was added over 60 min. Product crystallized from solution and the resulting slurry was cooled to 15°C over 1 h and then granulated for 4 h. The product was filtered and washed with water (3.75 L). The cake was blown dry with nitrogen for 30 min and then transferred to a vacuum oven and dried at 40°C for 12 h. The desired product, (11 ) (588 g, 1 .36 mol), was isolated in 89% yield.

¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .41-1 .63 (m, 6H), 1.71 -1.81 (m, 2H), 1.81 -1.94 (m, 1 H), 2.17-2.26 (m, 2H), 2.33 (s, 2H), 2.4 (td, J=1 1.7, 2.3, 2H), 2.92 (d, J=1 1 .8, 2H), 3.46 (s, 1 H), 3.71-3.84 (m, 4H), 3.91 -4.10 (m, 4H), 4.24 (d, J=5.9, 2H), 5.03-5.08 (m, 1 H), 6.50 (d, J=8.2, 1 H), 7.00 (d, J=8.2, 1 H), 7.38 (t, J=8.2, 1 H);

¹³C NMR (400 MHz, CDCI₃) δ ppm 29.1 1 , 33.10, 35.20, 36.92, 36.96, 56.15, 63.93, 67.14, 67.46, 68.27, 72.94, 74.06, 78.37, 103.17, 105.15, 131.71 , 152.71 , 166.02, 166.28;

LRMS 433.232 (m+1 ).

Example 2: Synthesis of iR)-4-ii4-i(4-itetrahvdrofuran-3-yloxy)benzord1isoxazol-3-yloxy)methyl)piperidin-1 -yl)methyl)tetrahvdro- 2H-pyran-4-ol

5-Hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one: Thionyl chloride (83.8 g, 0.71 mol) was slowly added to a solution of 2,6-dihydroxy-benzoic acid (77 g, 0.5 mol), acetone (37.7 g, 0.65 mol) and DMAP (3.1 g, 0.025 mol) in dimethoxyethane (375 mL). The mixture was stirred at RT for 7 h. The residue obtained after concentration under reduced pressure was dissolved in ethyl

acetate and washed with water and aqueous saturated sodium bicarbonate solution. The organic layer was dried (Na₂S0₄) and concentrated to afford 79 g desired product as a red solid (81 % yield). ¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .68 (s, 6H), 6.37 (dd, J=8, 0.8, 11-1) 6.56 (dd, J=8, 0.8, 1 H), 7.34 (t, J=8, 1 H), 10.27( brs, 1 H).

2,2-Dimethyl-5-[(R)-(tetrahydro-furan-3-yl)oxy]-benzo[1,3]dioxin-4-one:

Diethyl azodicarboxylate (130.5 g, 0.75 mol) was added in a dropwise fashion to a mixture of 5-hydroxy-2,2-dimethyl-benzo[1 ,3]dioxin-4-one (100 g, 0.51 mol), triphenylphosphine (196.5 g, 0.75 mol), and (S)-tetrahydro-furan-3-ol (44 g, 0.5 mol) in 600 ml. of anhydrous THF. The resulting mixture was stirred at RT for 18 h. The solvent was removed under reduced pressure and the crude material was purified on a silica gel flash column, eluting with petroleum ether/ ethyl acetate (15:1 -> 3:1 ). 86 g (65% yield) of product was isolated as a colorless oil. ¹ H NMR (400 MHz, CDCI₃) δ ppm 1.67 (s, 6H), 2.30 (m, 2H), 4.2 (m, 4H) 4.97 (m, 1 H), 6.49 (d, J=8.4, 1 H) 6.51 (d, J=8.4, 1 H), 7.39 (t,

J=8.4, 1 H).

2-Hydroxy-6-[(R)-(tetrahydro-furan-3-yl)oxy]-benzoic acid methyl ester: Potassium carbonate (134.8 g, 0.98 mol) was added to a solution of 2,2-dimethyl-5-[(R)-(tetrahydro-furan-3-yl)oxy]-benzo[1 ,3]dioxin-4-one (86 g, 0.33 mol) in 1 L methanol. The mixture was stirred at RT for 2 h, then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous ammonium chloride solution. The organic layer was dried (Na₂S0₄) and concentrated to afford 72 g of the product as a yellow solid (92% yield). ¹ H NMR (400 MHz, CDCI₃) δ ppm 2.20 (m, 2H), 3.99 (s, 3H), 4.80(m, 4H). 4.94 (m, 1 H), 6.31 (dd, J=8.4, 0.8, 1 H), 6.59 (dd, J=8.4, 0.8, 1 H), 7.30 (t, J=8.4, 1 H).

2,N-Dihydroxy-6-[(R)-(tetrahydro-furan-3-yl)oxy]-benzamide: Potassium carbonate (121 g. 0.867mmol) was added portionwise to a solution of hydroxylamine sulfate (120 g, 0.732 mol) in 360 ml. of water at 0°C. After stirring for 30 min, sodium sulfite (3.74 g, 0.029 mol) and a solution of 2-hydroxy-6-[(R)-(tetrahydro-furan-3-yl)oxy]-benzoic acid methyl ester (35 g, 0.146 mol) in 360 ml. of methanol were added and the mixture was stirred at 50°C for 30 h. Methanol was removed from the cooled reaction mixture under reduced pressure and the resulting aqueous layer was acidified with 2N HCI. The aqueous layer was extracted with ethyl acetate and the organic layer was dried (Na₂S0₄) and concentrated to afford 25 g (76% yield ) of the product as a yellow solid. ¹ H NMR (400 MHz, CDCI₃) δ ppm 2.00 (m, 1 H), 2.15 (m, 1 H), 3.80 (m, 4H), 5.05 (m, 1 H), 6.48 (d, J=8, 1 H), 6.49 (d, J=8, 1 H), 7.19 (t, J=8, 1 H), 10.41 (brs, 1 H), 1 1.49 (brs, 1 H); LRMS m/z 239 (m+1 ).

4-[(R)-(Tetrahydro-furan-3-yl)oxy]-benzo[d]isoxazol-3-ol: A solution of 2, N-dihydroxy-6-[(R)-(tetrahydro-furan-3-yl)oxy]-benzamide (25 g, 0.105 mol) in 250 ml. of THF was heated to 50°C. Carbonyl diimidazole was added portionwise and the resulting mixture was stirred at 50°C for 14 h. After cooling to RT, 100 ml. of 2N HCI was added and the aqueous layer was extracted with ethyl acetate. The combined organic layers were then extracted three times with 10% aqueous potassium carbonate. The potassium carbonate aqueous extracts were washed with ethyl acetate and then acidified to pH 2 – 3 with 2N HCI. The acidified aqueous layer was extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried (Na₂S0₄) and concentrated to afford 20 g of product as a yellow solid (43% yield). ¹ H NMR (400 MHz, CDCI₃) δ ppm 2.20 (m, 2H), 3.89 (m, 1 H), 4.01 (m, 3H), 5.05 (m, 1 H), 6.48 (d, J=7.6, 1 H). 6.92 (d, J=7.6, 1 H), 7.37 (t, J=7.6, 1 H); LRMS m/z 222 (m+1 ).

4-{4-[(R)-(Tetrahydro-furan-3-yl)oxy]-benzo[d]isoxazol-3-yloxymethyl}-piperidine-1-carboxylic acid tert-butyl ester: Diethyl azodicarboxylate (15.6 g, 0.09 mol) was added to a mixture of 4-[(R)-(tetrahydro-furan-3-yl)oxy]-benzo[d]isoxazol-3-ol (10 g, 0.045 mol), 4-hydroxymethyl-piperidine-1 -carboxylic acid tert-butyl ester (1 1.6 g, 0.054 mol) and triphenylphosphine (23.5 g, 0.09 mol) in 300 mL THF. After the addition was complete the mixture was heated at reflux for 18 h. After concentration in vacuo, the crude product was purified on a silica gel flash column, eluting with petroleum ether/ ethyl acetate (15:1 -» 5:1 ) to afford 22 g of the product as an oil (51 % yield). ¹ H NMR (400 MHz, CDCI₃) δ ppm 1.25 (m, 2H), 1.39 (s, 9H), 1.76 (m, 2H), 1.99 (m, 1 H). 2.15 (m, 2H), 2.70 (bt, J=1 1.6, 2H), 3.95 (m, 4H). 4.13 (m, 2H). 4.34 (d J=6.4, 2H), 4.98 (m, 1 H), 6.43 (d, J=8, 1 H), 6.93 (d, J=8, 1 H), 7.31 (t, J=8, 1 H).

3-(Piperidin-4-ylmethoxy)-4-[(R)-(tetrahydro-furan-3-yl)oxy]-benzo[d]isoxazole: A 0°C solution of 4-{4-[(R)-(tetrahydro-furan-3-yl)oxy]-benzo[d]isoxazol-3-yloxymethyl}-piperidine-1 -carboxylic acid tert-butyl ester in 500 mL ether was treated with a saturated solution of HCI (g) in 200 mL ether. After addition was complete, the mixture was warmed to RT and stirred for 16 h. The reaction mixture was filtered. The white solid was washed with ethyl acetate followed by ether and dried to yield 15 g (81 % yield) of the desired product as a white solid. ¹ H NMR (400 MHz, CD₃OD) 5 ppm 1 .51 – 1.69 (m, 2 H) 2.04 – 2.19 (m, 3 H) 2.22 – 2.37 (m, 2 H) 2.99 – 3.14 (m, 2 H) 3.40 – 3.51 (m, 2 H) 3.85 – 4.02 (m, 4 H) 4.25 – 4.31 (m, 2 H) 5.17 (td, J= >1^ , 1 .56 Hz, 1 H) 6.72 (d, J=8.00 Hz, 1 H) 7.01 (d, J=8.59 Hz, 1 H) 7.47 (t, J=8.20 Hz, 1 H); LRMS m/z 319 (m+1 ).

4-(4-{4-[(R)-(Tetrahydro-furan-3-yl)oxy]-benzo[d]isoxazol-3-yloxymethyl}-piperidin-1-ylmethyl)-tetrahydro-pyran-4-ol: 1 ,6-Dioxa-spiro[2.5]octane (Focus Synthesis; 9.7 g, 0.084 mol) and triethylamine (8.6 g, 0.084 mol) were added to a solution of 3-(piperidin-4-ylmethoxy)-4-[(R)-(tetrahydro-furan-3-yl)oxy]-benzo[d]isoxazole (15 g, 0.042 mol) in 200 mL methanol. The resulting solution was heated at reflux for 18 h. The cooled mixture was concentrated and ethyl acetate and water were added to the residue. The layers were separated and the organic extracts were washed with brine, dried (Na₂S0₄) and concentrated to provide 17 g crude product as a yellow oil. The crude material was purified by prep HPLC to afford 10 g of the desired product as a white solid. (50% yield).

¹ H NMR (400 MHz, CDCI₃) δ ppm 1.41 -1.63 (m, 6H), 1.71-1.81 (m, 2H), 1 .81 -1 .94 (m, 1 H), 2.17-2.26 (m, 2H), 2.33 (s, 2H), 2.4 (td, J=1 1 .7, 2.3, 2H), 2.92 (d, J=1 1.8, 2H), 3.46 (s, 1 H), 3.71-3.84 (m, 4H), 3.91-4.10 (m, 4H), 4.24 (d, J=5.9, 2H), 5.03-5.08 (m, 1 H), 6.50 (d, J=8.2, 1 H), 7.00 (d, J=8.2, 1 H), 7.38 (t, J=8.2, 1 H);

¹³C NMR (101 MHz, CDCI₃) δ ppm 29.1 1 , 33.10, 35.20, 36.92, 36.96, 56.15, 63.93, 67.14, 67.46, 68.27, 72.94, 74.06, 78.37, 103.17, 105.15, 131.71 , 152.71 , 166.02, 166.28.

PAPER

Two Routes to 4-Fluorobenzisoxazol-3-one in the Synthesis of a 5-HT₄Partial Agonist

Daniel W. Widlicka^*^†, John C. Murray^†, Karen J. Coffman^†, Chunguang Xiao^‡, Michael A. Brodney^†, Joseph P. Rainville^†, and Brian Samas^†

^† Groton Laboratories, Worldwide Research & Development, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340,United States

^‡ Porton Fine Chemical, 1 Fine Chemical Zone, Chongqing Chemical Industrial Park, Changshou, Chongqing 401221China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00389

Publication Date (Web): February 2, 2016

*E-mail: daniel.w.widlicka@pfizer.com.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00389

A potent 5-HT₄ partial agonist, 1 (PF-04995274), targeted for the treatment of Alzheimer’s disease and cognitive impairment, has been prepared on a multi-kilogram scale. The initial synthetic route, that proceeded through a 4-substituted 3-hydroxybenzisoxazole core, gave an undesired benzoxazolinone through a Lossen-type rearrangement. Route scouting led to two new robust routes to the desired 4-substituted core. Process development led to the efficient assembly of the API on a pilot plant scale under process-friendly conditions with enhanced throughput. In addition, crystallization of a hemicitrate salt of the API with pharmaceutically beneficial properties was developed to enable progression of clinical studies.

REFERNCES

Noguchi, H.; Waizumi, N. Preparation of benzisoxazole derivatives for treatment of 5-HT4 mediated disorders. PCT Int. Appl. WO/2011/101774 A1, 20110825

////////PF-04995274, PF 04995274, PFIZER, Alzheimer’s type dementia, PHASE 1

c1cc2c(c(c1)O[C@@H]3CCOC3)c(no2)OCC4CCN(CC4)CC5(CCOCC5)O

WO 2016011767, New patent, Clopidogrel, SHENZHEN SALUBRIS/ HUIZHOU SALUBRIS

February 2, 2016 8:31 am / Leave a comment

WO 2016011767

SHENZHEN SALUBRIS PHARMACEUTICALS CO.,LTD [CN/CN]; 37F Main Tower, Lvjing plaza, Che Gong Miao, No. 6009 Shennan Road, Futian District Shenzhen, Guangdong 518040 (CN).
HUIZHOU SALUBRIS PHARMACEUTICALS CO.,LTD. [CN/CN]; No.42, West petrochemical Avenue, West District，Huizhou DayaBay Huizhou, Guangdong 516083 (CN)

LI, Haidong; (CN).
TAN, Duanming; (CN).
WANG, Hai; (CN)

Provided is a preparation method for high purity clopidogrel and salt thereof. In the present method, inorganic acid solution is used to wash an organic phase containing clopidogrel till a specific pH value range is reached; during the post-processing stage, impurities including TTP can be removed from the clopidogrel product. The ensuing refining step can be avoided, thereby simplifying production techniques and ensuring the quality of the clopidogrel product.

Clopidogrel, molecular formula: C ₁₆ H ₁₆ ClNO ₂ S, it is an inhibitor of induced platelet aggregation by inhibiting platelet aggregation reduces the chance of arterial obstruction, to prevent stroke and heart attack efficacy, and can effectively treatment and prevention of atherosclerosis. Clopidogrel clinical use for right-handed body, clinical sulfate administered in the form of finished products on the domestic market clopidogrel main Plavix (Plavix) and Techno.

Currently it reported a variety of synthetic methods clopidogrel or a salt thereof, may be optically active or racemic α- substituted-o-chlorophenyl-acetate as a raw material, and 4,5,6,7-tetrahydro-thieno [3, 2-c] pyridine or a salt thereof under basic conditions to afford the optically active or racemic clopidogrel or a salt thereof, and further in line with the preparation of pharmaceutically acceptable Clopidogrel sulfate API standards.

Chinese Patent CN200810142388.3 using α- dextrose substituted benzenesulfonic substituted-o-chlorophenyl-acetate prepared above dextrorotatory clopidogrel free base, the process with ethyl acetate as the reaction solvent, followed by treatment using the organic phase washed with water The method of removing impurities.

Chinese Patent CN201310167933.5 prepared using the above racemic Clopidogrel hydrochloride, the method with dichloromethane as the solvent, after the reaction was washed with water and the organic layer was evaporated to dryness, the salt in ethyl acetate to give the product.

If the above process synthesis optically active or racemic clopidogrel or a salt thereof, the reaction system there is usually residual starting material 4,5,6,7-tetrahydro-thieno [3,2-c] pyridine (referred to as “TTP “) or a salt thereof, according to the method disclosed in the prior art, after the treatment of the synthesis process commonly used water extraction – water / weak alkaline solution washed – salt-forming method, since the same TTP and clopidogrel alkaline organics neutral or alkaline solution solubility difference, and is in an acidic solution with a salt, and therefore only the wash water or weak alkaline solution generally can not be divisible TTP, usually larger residues.

Due to the special nature of clopidogrel API, making it even within the scope of quality control requirements of the quality standards, there are still unstable phenomenon. In the standard range of high impurity content on the one hand it can significantly affect the stability of the product, on the other hand will increase the side effects of the subsequent steps. Thus, the prior art is usually removed after the reaction by purification methods such as recrystallization include TTP including impurities, but it will increase the preparation process, in addition to loss of product due to some of the products will remain in the mother liquor caused.

From the above, in a more convenient way to remove impurities, higher purity, better stability of clopidogrel and its salts are existing technology is not yet resolved. The present invention is a departure from the deficiencies of the prior art, provides a method for preparing high purity clopidogrel and its salts, which can be removed after the treatment stage the majority of clopidogrel impurities in the product, avoiding the subsequent refining step In simplifying the production process, while ensuring the quality of clopidogrel products.

Example 1 (racemic clopidogrel hydrochloride monohydrate) Example

China Patent CN201310167933.5 using the method disclosed in Example 19 preparation of racemic clopidogrel. In TTP and α- bromo-o-chlorophenyl acetate The reaction was refluxed for 4h after the organic phase was separated, the methylene chloride solution of racemic clopidogrel. With stirring was added 5% hydrochloric acid (pH approximately 0), the aqueous phase until the pH stabilized around 4. The phases were separated and the organic phase the solvent was evaporated under reduced pressure, 75ml of ethyl acetate was added to dissolve, added dropwise with stirring 6.6g 36% hydrochloric acid to precipitate crystals. 2h After filtration, the filter cake washed with ethyl acetate. After drying in vacuo to give 17.2g white crystals. Using the same test conditions and CN201310167933.5 testing product purity of 99.8% containing impurities TTP 0.011% (area normalization method).

Example 2 (racemic clopidogrel hydrochloride monohydrate)

China Patent CN201310167933.5 using the method disclosed in Example 19 preparation of racemic clopidogrel. In TTP with α- bromo-o-chlorophenyl acetate reflux 4h reaction after the separation of the organic phase. The organic phase the solvent was evaporated under reduced pressure, 75ml of ethyl acetate was added to dissolve. 5% hydrochloric acid was added with stirring, until the aqueous phase pH stabilized around 3. Phase, the organic phase was added dropwise with stirring to 6.6g 36% hydrochloric acid to crystallize. 2h After filtration, the filter cake washed with ethyl acetate. After drying under vacuum to give 17.0g white crystals. Product purity was 99.7% containing impurities, TTP 0.014% (detecting method as in Example 1).

Example 3 (right-handed clopidogrel hydrogen sulfate)

The TTP hydrochloride 26.4g (0.15mol), ethyl acetate 50ml, 80ml mixing water and potassium carbonate 22g, stirred for 20 minutes. Joined by R-α- methyl tosylate Chloromandelic 34.1g (0.1mol) mixture of ethyl acetate and 50ml solution. The reaction temperature was raised to 45 ℃ 4h, then the reaction was heated to 60 ℃ to R-α- methyl tosylate Chloromandelic completely consumed (about 3h). Cooled to room temperature phase.

The organic phase was added with stirring to a 5% aqueous sulfuric acid until the pH of the aqueous phase is stable at around 3. After stirring 10min static phase separation. Then dried over anhydrous magnesium sulfate, and evaporated to dryness to give 30.6g dextrose clopidogrel hydrogen sulfate. Purity 98.6% by HPLC, spectrum display free of impurities TTP.

//////WO 2016011767, New patent,Clopidogrel, SHENZHEN SALUBRIS, HUIZHOU SALUBRIS

WO 2016014324, New Patent, Omarigliptin, MERCK SHARP & DOHME CORP

February 2, 2016 7:24 am / Leave a comment

Omarigliptin , MK-3102

WO2016014324, PROCESS FOR PREPARING CHIRAL DIPEPTIDYL PEPTIDASE-IV INHIBITORS

MERCK SHARP & DOHME CORP. [US/US]; 126 East Lincoln Avenue Rahway, New Jersey 07065-0907 (US).

CHUNG, John, Y. L.; (US).
PENG, Feng; (US).
CHEN, Yonggang; (US).
KASSIM, Amude Mahmoud; (US).
CHEN, Cheng-yi; (US).
MAUST, Mathew; (US).
MCLAUGHLIN, Mark; (US).
ZACUTO, Michael, J.; (US).
CHEN, Qinghao; (US).
TAN, Lushi; (US).
SONG, Zhiguo Jake; (US).
CAO, Yang; (US).
XU, Feng; (US)

A process for preparing a compound of structural Formula Ia: comprising Boc deprotection with TFA of, reductive amination of:.

The present invention is directed to a novel process for the preparation of omarigliptin, (2R,35^,,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3 -amine, a dipeptidyl peptidase-IV (DPP-4) inhibitor, for the treatment of Type 2 diabetes, and related intermediates.

BACKGROUND OF THE INVENTION

Syntheses of omarigliptin have previously been described in PCT international patent applications numbers WO 2010/056708 and WO2013/003250. The process described in WO 2010/056708 does not result in a favorable yield of the compound of structural Formula la, as it results in a racemic mixture. WO2013/003250 describes the following scheme to make the compound of structural Formula la, an intermediate for synthesizing omarigliptin:

In WO2013/003250, synthesis of the compound of structural Formula la involves using benzenesulfonic acid (BSA) to remove the Boc protecting group of the compound of structural Formula 1, by first forming a BSA salt of the compound of structural Formula la. The BSA salt is then isolated and undergoes reductive amination with Boc -ketone of the compound of structural Formula 7, to produce the compound of structural Formula la, as a 19: 1 diastereomeric mixture. The BSA mediated Boc deprotection requires up to 72 h to reach full conversion.

An alternative process which eliminates the need to isolate the BSA salt of the compound of Formula la and reduces the overall reaction time of the process is desired. The inventors have now discovered a process for making the compound of structural Formula la which eliminates the step of isolating a salt of the compound of structural Formula la and reduces the overall reaction time. The present process also produces an end-of reaction homogeneous solution via reductive amination, which facilitates crystallization of the compound of structural Formula la. The described process also improves the diastereoselectivity, overall yield, cost and cycle time over the process described in WO2013/003250.

WO2013/003250 also describes the Boc deprotection of the compound of Formula la to produce omarigliptin (Formula I) shown below. As described in WO2013/003250, the Boc deprotection of the compound of Formula la involves aging the substrate in aqueous sulfuric acid in DMAc at 30 °C for 15-20 h, then working up with ammonium hydroxide. This work up produces large amounts of poorly soluble ammonium sulfate which co-crystallizes with the desired product. As a result, isolation of the desired product requires a long cycle time for filtration, washing and drying.

Formula I (omarigliptin)

Because the processes described herein use trifluoroacetic acid with or without a co-solvent for the transformation of the compound of Formula la to omarigliptin, which offers good solubility for the compound of Formula la, omarigliptin is achieved with fast reaction kinetics and good purity profiles.

the compound of structural Formula 1 is prepared by the following processes:

reagents

and,

or alternatively

10 R = Ms

X=OAc

SCHEME 3: Synthesis of the Boc Ketone

16 17 18 19

IPA, H₂Q ,

¹⁾⁹⁵⁶

Step 1 : As

A round bottom flask was charged with ligand L (0.829 g), Cu(II) propionate

monohydrate (0.402 g) (or Cu(II) acetate (0.31 g) or CuCl or CuCl₂) and EtOH (350 ml) and agitated at room temperature for lh. 2,4-Difluorobenzaldehyde (100.0 g) was added followed by DABCO (2.368 g) (or 2,4-dimethylpiperizine) and the mixture was cooled to -5 – -15 °C. Cold (0°C) nitromethane (190 ml or 215 g) was added slowly to the cold solution and the solution was aged at -5 to -15 °C for 20-24 h and at 0 °C for 2-4h. 5 wt% EDTA^»2Na (500 ml) followed by

water (200 mL) and MTBE (1.0 L) was added to the cold solution, and the temperature was raised to 20°C. The layers were separated and the organic layer was washed with additional 5 wt% EDTA^»2Na (500 ml), followed by water (50 mL) and brine (250 mL). The organic layer, containing Compound 17, was concentrated to remove nitromethane, then the solvent was switched to THF.

Step 2: Michael-Lactolization – Nitro lactol

To Compound 17 in 2 volumes of THF (258 mL) from Step 1 under 2 and cooling at 0 °C, 1 equivalent of Hunig’s base was added. 1.15 equivalents of acrolein was added over 1 h via syringe pump at 0-5 °C. The reaction was stirred at -10-0 °C overnight. The resulting mixture was used directly in the next step.

Alternatively, the mixture was concentrated at 0-5 °C to remove excess acrolein, then the residue was flushed with acetonitrile until Hunig’s base and water are mostly removed. The residue was taken up in 8 volumes of acetonitrile and used directly in the next step.

Alternatively, at the end of the reaction the mixture was worked up by diluting with MTBE and washing with aqueous citric acid solution, and aqueous NaHCC solution, and the solvent was switched to acetonitrile. Alternatively, the end reaction mixture was taken forward directly to the next step.

Step 3: Dehydration – Nitro dihydropyrans

1.1 Equivalents of TEA was added to the acetonitrile solution of lactol 18 from Step 2 followed by 1.2 equivalents of mesyl chloride and 1.2 equivalents of S-collidine under < +10 °C . The reaction was aged at 10°C for 0.5-1 h. Alternatively, the end of the reaction mixture from Step 2 was cooled to between -20 °C to 0 °C. Two equivalents of S-collidine and 1.4 equivalents of mesyl chloride were then added. The mixture was heated to 36 °C and aged overnight. The mixture was cooled to room temperature. 15 volumes of MTBE was added and the solution was

washed with 3 volumes 10 wt% citric acid and 6 volumes water, 10 volumes water, then 3 volumes of 5% aHC03 solution and 6 volumes water. The organic was concentrated with 20 volumes of MTBE using 10 volumes MTBE. The organic solution was stirred with 20-30 wt% AQUAGUARD for 2 hours at room temperature. The mixture was filtered and washed with 2 volumes of MTBE.

Step 4: Dynamic Kinetic Resolution (DKR) crystallization – rraws-nitro-dihydropyran (19t)

The organic MTBE solution of Step 3 was solvent switched to 2 volumes of IPA and the final volume was -300 mL. 10 Mol% of TEA (or DAB CO or morpholine or DMAP) was added. Then water (1 15 mL) was slowly added over 3 hours. The slurry was filtered, washed with 80/20 IP A/water (2×100 mL) and vacuum dried under N₂.

Step 5: Hydroboration/oxidation – Trans-nitro-pyranol

To a vessel charged with /raws-nitro-dihydropyran (10 g), MTBE (100 mL) was added under nitrogen. The mixture was stirred at room temperature to give a clear orange solution. The solution was cooled to +2 °C and borane dimethyl sulfide complex (9.55 ml) was added. The clear solution was aged for 2-5h until >99% conversion by HPLC analysis. The reaction was slowly quenched with water (7.25 ml) keeping at < +9 °C. After the solution was aged at 5°C for 5 min, water (78 mL) was added at < +13 °C. Solid sodium percarbonate (13.26 g, 84 mmol) was added. The suspension was stirred at 5 °C for 15h. The mixture was transferred to a separatory funnel with the aid of 60 mL MTBE and 20 mL water. The mixture was allowed to warm to room temperature. The aqueous phase was back-extracted with 40 mL MTBE. The combined organic phase was washed once with 30 mL half saturated sodium chloride solution, once with 15 mL brine and 15 mL 0.2N HC1, and once with 30 mL half-saturated sodium chloride solution. The organic layer was dried over a2S04. The organic was filtered, washed with 10 mL MTBE and concentrated to an oil. The oil was diluted to 200 mL for a 0.191M solution.

Step 6: Nitro Reduction/Boc protection – Pyranol

A 3 -neck jacketed round bottom flask equipped with overhead stirrier was charged with 0.191M (5R,6S)-5-nitro-pyran-3-ol (119 ml) (Compound 20) in ethanol and ethanol (32 ml). The solution was cooled to 1 1-12 °C. Cold 6N HC1 (19.55 ml, 1 17 mmol) was added at <

+17°C. Zinc dust (12.93 g) was added in five portions (5×2.59g) at < +26 °C. The mixture was stirred at 12 °C for 22 h. 1M K₂C0₃ (76 mL) was added in one portion. MTBE (59 mL) was added then EDTA 2K 2H₂0 (22.55 g) was added over 10 min at < +14 °C. To the solution 45 wt% KOH (4.86 mL) solution was added. The solution was cooled to 5 °C, and 1.1 equivalents of B0C2O (5.46 g) was added. The solution was rinsed with MTBE (10 mL) and stirred at 5 °C for 2h, then at 12 °C for 16h, and then at 24 °C for lOh until >99.5% conversion. The solution was transferred to a separatory funnel with the aid of MTBE (30 mL) and water (5 mL). The organic layer was filtered and washed with MTBE (20 mL). The organic filtrate was concentrated. MTBE (60 mL), water (30 mL) and saturated sodium chloride solution (15 mL) were added. The mixture was warmed in a 30 °C bath to dissolve solid, and then concentrated. The concentrate was flushed with toluene in a 60 °C bath, then concentrated. Toluene (8.4 mL) was added and the mixture was heated to 80 °C. Heptane (70.8 mL) was added over lh at 80 °C, then cooled slowly to room temperature. The mixture was filtered and washed with 1 :2 toluene/heptane (23.55 mL), filterated and vacuum dried under nitrogen until a constant weight.

The purity could be further upgraded by the following procedure: a round bottom flask was charged with the product of Step 6 (7.069 g) from above. EtOH (21 mL) was added and the mixture was heated to 45 °C. Water (31.5 mL) was slowly added over 1 h at 45 °C. The mixture was aged for lh. Water (31.5 mL) was added in one portion, then cooled slowly to room temperature and aged overnight. The slurry was filtered and washed with 1 :3.5 EtOH/water (23.56 mL). Crystals were vacuum dried under nitrogen until a constant weight.

Alternatively, Compound 20 was reduced with 100 psi hydrogen in 20 volume wet THF in the presence of 10-30 wt% Raney nickel at 50 °C. Then the reaction mixture was basified with 2 equivalent of K2CO₃ and a slight execess B0C2O to afford crude Compound 21 after aqueous work up.

Compound 7 was obtained from 21via oxidation as described in WO2013/003250.

Boc-mesyl-pyrazole solid 1 was added to 2.5 volumes of TFA at 0-2 °C, over 2-3 minutes under nitrogen, followed by 0.5 volume of TFA rinse. Conversion to TFA salt was complete within 0.5-lh at 1-2 °C. DMAc (14 vol) followed by triethylamine (5 equivalents or 2.3 volumes) were slowly added to the TFA reaction mixture at 0 °C maintaining < +20 °C. Boc-ketone 7 (0.89 equivalent) was then added at -15 °C followed by solid NaBH(OAc)₃ (1.4 equivalents) which was added in three portions over lh. The reaction solution was aged at -15 °C overnight. The solution was then warmed to 22 °C, and after aging for 2-5 h. Diastereomeric ratio was > 96.5:3.5.

The solution was seeded with Boc amine 1 wt% at 22 °C and stirred at 22-40 °C for 2-4 h. 0.36 volume 28% ammonium hydroxide was added over 2-4 h, then, 3.64 volumes 28% ammonium hydroxide was added over 4-10h at 22-60 °C. After cooling to 22 °C, the batch was filtered, washed with 5: 1 DMAc/water, then water. The wet cake was vacuum dried under nitrogen at ambient affording the product. Diastereoselectivity was > 30: 1.

Boc Deprotection of Formula la

A reactor was charged with 2.5 X (by volume) of trifluoroacetic acid. The batch was cooled to 5-10 °C. The reactor was then charged with 0.4 X (by volume) water. The batch was cooled to 0-5 °C. The reactor was then charged with 1 equivalent (1 kg) of the compound of Formula la over 0.5-lh while maintaining the temperature between 0 -5°C. The reactor was then charged with 0.5 X (by volume) trifluoroacetic acid to reactor while maintaining the temperature between 0-5°C. The batch was then heated between 15-20°C and aged for 2-2.5 h. The batch was then cooled to between 5-10°C. A crystallizer was charged with water 5.0 X (by volume) and 0.1 X (by volume) of ammonia water and adjusted to between 3-13°C. To generate a seed bed, Compound I seed (lwt% vs la) was added and the temperature as adjusted to between 3-13°C. A solution of ammonia water 3.8 X (by volume) and of the compound of Formula la was added simultaneously to the seed bed over 2.5 – 3.5 hours while maintaining temperature at 3-13°C and pH -9-10. The batch was aged for at least 30 minutes and then filtered. The resulting crystals were washed with 3. OX (by volume) water at 3 – 13°C twice and vacuum dried at < 50°C to afford the compound of formula I.

//////WO 2016014324, New Patent, Omarigliptin, MERCK SHARP & DOHME CORP, MK-3102

New TRPV1 Antagonist From Neurogen Corporation

February 1, 2016 3:50 am / Leave a comment

MK ? NGD?

MK 2295; NGD 8243 may be???????

CAS 878811-00-8 FREE FORM

Molecular Formula:	C₂₇H₃₁FN₆O₂
Molecular Weight:	490.572443 g/mol

6-[(3R)-4-[6-(4-fluorophenyl)-2-[(2R)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]-3-methylpiperazin-1-yl]-5-methylpyridine-3-carboxylic acid

6-{4-[6-(4-Fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinic acid

3-Pyridinecarboxylic acid, 6-[(3R)-4-[6-(4-fluorophenyl)-2-[(2R)-2-methyl-1-pyrrolidinyl]-4-pyrimidinyl]-3-methyl-1-piperazinyl]-5-methyl-

Neurogen Corp INNOVATOR

MESYLATE

CAS 1855897-95-8

6-((R)-4-(6-(4-Fluorophenyl)-2-((R)-2-methylpyrrolidin-1-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)-5-methylnicotinic acid methanesulfonic acid salt

white solid. ¹H NMR (CD₃OD, 400 MHz) δ 1.37 (d, 3H, J= 6.4 Hz), 1.48 (d, 3H, J = 6.7 Hz), 1.84 (m, 1H), 2.09 (m, 1H), 2.17–2.25 (m, 2H), 2.42 (s, 3H), 2.66 (s, 3H), 3.10 (dt, 1H, J = 12.3 and 3.3 Hz), 3.28 (dd, 1H, J = 13.1 and 3.7 Hz), 3.65–3.72 (m, 3H), 3.78 (m, 1H), 3.87 (m, 1H), 4.49 (m, 1H), 4.63 (m, 3H), 4.96 (br m, 1H), 6.61 (s, 1H), 7.32 (m, 2H), 7.82 (m, 2H), 8.05 (m, 1H), 8.69 (d, 1H, J = 1.9 Hz);

¹³C NMR (CD₃OD, 125 MHz) δ 19.4, 24.5, 33.5, 39.6, 41.5, 48.6, 50.0, 50.9, 54.1, 56.9, 94.8, 117.3 (d, J = 22.5 Hz), 122.1, 125.0, 130.1 (d, J = 3.3 Hz), 131.8 (d, J = 8.9 Hz), 142.1, 148.7, 153.1, 153.3, 162.4, 165.4, 166.4, (d, J = 251.3 Hz), 168.8;

¹⁹F NMR (CD₃OD, 470 MHz) δ −108.6.

Anal. Calcd For C₂₈H₃₅FN₆O₅S: C, 57.32; H, 6.01; N, 14.32. Found: C, 57.34; H, 6.13; N, 14.29.

Activated by a wide range of stimuli such as capsaicin, acid, or heat, the transient receptor potential vanilloid-1 (TRPV1) has been identified as a potential treatment for chronic pain.TRPV1 is a highly characterized member of the TRP cation channel family believed to be involved in a number of important biological roles and plays a role in the transmission of pain.TRPV1 activation inhibits the transition of pain signals from the periphery to the central nervous system (CNS), leading to the possible development of analgesic and anti-inflammatory agents. TRPV1 antagonists have also been evaluated in multiple clinical trials where hyperthermic effects seen preclinically are also observed in humans

PATENT

http://www.google.com.na/patents/US20110003813

6-{4-[6-(4-Fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinic acid 1. 1-(5-Bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine

Heat a solution of 2,5-dibromo-3-methyl-pyridine (Chontech Inc., Waterford, Conn.) (2.0 g, 7.97 mmol), (R)-2-methyl-piperazine (ChemPacific Corp., Baltimore, Md.; 3.2 g, 31.9 mmol) in DMA at 130° C. for 16 h. Partition the reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na₂SO₄) and concentrate under reduced pressure to give 1-(5-bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine as a solid.

2. 2,4-dichloro-6-(4-fluorophenyl)pyrimidine

Dissolve 4-fluorobromobenzene (8.75 g, 0.05 moles) in anhydrous ether (80 mL) under nitrogen atmosphere and cool to −78° C. Add dropwise 1.6 M n-BuLi (34 mL, 0.055 moles) and stir at −78° C. for 45 min. Dissolve 2,4-dichloropyrimidine (7.45 g, 0.05 moles) in Et₂O (100 mL) and add dropwise to the reaction mixture. Warm the reaction mixture to −30° C. and stir at this temperature for 30 min followed by 0° C. for 30 min. Quench the reaction mixture with AcOH (3.15 mL, 0.055 moles) and water (0.5 mL, 0.027 moles) dissolved in THF (5.0 mL). Add dropwise a THF (40 mL) solution of DDQ (11.9 g, 0.053 moles) to the reaction mixture. Bring the reaction mixture to room temperature and stir at room temperature for 30 min. Cool the reaction mixture to 0° C., add 3.0 N aq. NaOH (35 mL) and stir for 30 min. Decant the organic layer from the reaction mixture and wash the brown solid with Et₂O (3×100 mL). Combine the organic layers, wash several times with saturated NaCl solution and dry with MgSO₄. Filter and evaporate under vacuum to afford a brown colored solid. Purify by flash column chromatography using 5% EtOAc/hexane to afford the title product as a white solid.

3. 4-[4-(5-Bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-2-chloro-6-(4-fluoro-phenyl)-pyrimidine

Heat a mixture of 2,4-dichloro-6-(4-fluoro-phenyl)-pyrimidine (6.0 g, 24.7 mmol), 1-(5-bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine (7.0 g, 25.9 mmol) and K₂CO₃(6.8 g, 49.4 mmol) in DMA at 60° C. for 16 h. Partition the mixture between EtOAc and water, dry (Na₂SO₄) the organic layer and concentrate under reduced pressure. Purify with flash silica gel column eluting with 15% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound.

4. 4-[4-(5-Bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-6-(4-fluoro-phenyl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidine

Heat a mixture of 4-[4-(5-bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-2-chloro-6-(4-fluoro-phenyl)-pyrimidine (7.7 g, 16.2 mmol), (R)-2-methylpyrrolidine hydrobromide [prepared essentially as described by Nijhuis et. al. (1989) J. Org. Chem. 54(1):209] (3.5 g, 21.1 mmol) and K₂CO₃(5.1 g, 37.3 mmol) in DMA at 110° C. for 16 h. Partition the mixture between EtOAc and water, dry (Na₂SO₄) the organic layer and concentrate under reduced pressure. Purify with flash silica gel column eluting with 10% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound.
5. 6-{4-[6-(4-Fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinonitrile
To a mixture of 4-[4-(5-bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine (700 mg, 1.33 mmol) and Zn(CN)₂(94 mg, 0.799 mmol) in DMF, add Pd(PPh₃)₄(77 mg, 0.067 mmol). Purge the reaction mixture for 10 min with dry N₂. Heat the stirring reaction mixture overnight at 80° C., cool to room temperature and partition between water and EtOAc. Dry the solution (Na₂SO₄), concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:1) to afford the title compound as a white solid.
6. 6-{4-[6-(4-Fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinic acid
Heat a solution of 6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinonitrile (100 mg, 0.212 mmol) in 12 M HCl for 3 hours at 90° C. Concentrate the mixture under reduced pressure. Add a small amount of water, adjust the pH to 6-7, and collect the resulting white precipitate to afford the title compound as a off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 1.24 (m, 6H, 2×CH₃))_;1.61 (m, 1H,); 1.84 (m, 1H); 1.98 (m, 2H); 2.34 (s, 3H, Ar—CH₃); 2.91 (m, 1H); 3.08 (m, 1H); 3.26 (m, 2H); 3.56 (m, 2H); 3.74 (m, 1H); 4.21 (m, 1H); 4.35 (m, 1H); 4.74 (m, 1H); 6.57 (s, 1H); 7.26 (m, 2H); 7.91 (d, 1H, J=3 Hz); 8.15 (m, 2H); 8.60 (d, 1H, J=3 Hz).

END…………………

MESYLATE NMR

¹H NMR (CD₃OD, 400 MHz) δ 1.37 (d, 3H, J= 6.4 Hz), 1.48 (d, 3H, J = 6.7 Hz), 1.84 (m, 1H), 2.09 (m, 1H), 2.17–2.25 (m, 2H), 2.42 (s, 3H), 2.66 (s, 3H), 3.10 (dt, 1H, J = 12.3 and 3.3 Hz), 3.28 (dd, 1H, J = 13.1 and 3.7 Hz), 3.65–3.72 (m, 3H), 3.78 (m, 1H), 3.87 (m, 1H), 4.49 (m, 1H), 4.63 (m, 3H), 4.96 (br m, 1H), 6.61 (s, 1H), 7.32 (m, 2H), 7.82 (m, 2H), 8.05 (m, 1H), 8.69 (d, 1H, J = 1.9 Hz);

¹⁹F NMR (CD₃OD, 470 MHz) δ −108.6.

PATENT

http://www.google.ga/patents/WO2006026135

Scheme 1

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Scheme 7

Scheme 8

Scheme 9

Scheme 10

Scheme 14

Scheme 15

Scheme 16

Scheme 17

Scheme 18

Scheme 19

Scheme 20

6-{4-[6~(4-Fluoro-phenyl)-2-(2~methyl-pyrrolidin-l-yl)-pyrimidin-4-yl]-3-(R)-met}τyl- piperazin-l-yl}-5-methyl-nicotinic acid

Heat a solution of 6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-l-yl)-pyrimidin-4-yl]- 3-(R)-methyl-piperazin-l-yl}-5-methyl-nicotinonitrile (100 mg, 0.212 mmol) in 12 M HCl for 3 hours at 9O⁰C. Concentrate the mixture under reduced pressure. Add a small amount of water, adjust the pH to 6-7, and collect the resulting white precipitate to afford the title compound as a off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 1.24 (m, 6H, 2xCH₃)); 1.61 (m, 1Η,); 1.84 (m, 1Η); 1.98 (m, 2Η); 2.34 (s, 3H, Ar-CH₃); 2.91 (m, 1Η); 3.08 (m, 1Η); 3.26 (m, 2Η); 3.56 (m, 2H); 3.74 (m, IH); 4.21 (m, IH); 4.35 (m, IH); 4.74 (m, IH); 6.57 (s, IH); 7.26 (m, 2H); 7.91 (d, IH, J = 3Hz); 8.15 (m, 2H); 8.60 (d, IH, J = 3Hz).

PAPER

Development of a Multikilogram Scale Synthesis of a TRPV1 Antagonist

Jeffrey T. Kuethe^*, Michel Journet, Zhihui Peng, Dalian Zhao, Arlene McKeown, and Guy R. Humphrey

Department of Process Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00388

Publication Date (Web): January 13, 2016

*E-mail: Jeffrey_Kuethe@merck.com.

Abstract

A highly efficient, regioselective five-step synthesis of the TRPV1 antagonist 1 is described. The coupling of piperazine 7 with dichloropyrimidine 8 proceeded via a regioselective Pd-mediated amination affording product 11 in excellent yield. Conversion of the penultimate product 14 afforded 1 through formation of a magnesium ate complex and trapping with CO₂.

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.5b00388

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.5b00388/suppl_file/op5b00388_si_001.pdf

Patent	Submitted	Granted
Substituted biaryl piperazinyl-pyridine analogues [US7662830]	2006-06-08	2010-02-16
SUBSTITUTED BIARYL PIPERAZINYL-PYRIDINE ANALOGUES [US2011003813]	2011-01-06

Blum, C. A.; Brielmann, H.; Chenard, B. L.; Zheng, X. Preparation of substituted biaryl piperazinyl-pyridine analogues as capsaicin modulators. PCT Int. Appl. WO 2006026135 A2 20060309, 2006.

Neurogen Corporation, a Subsidiary of Ligand Pharmaceuticals Inc., 11119 North Torrey Pines Road, Suite 200, La Jolla, CA 92037, U.S.A.

Neurogen and Merck Agreement for Next-Generation Pain Drugs Consummated

Source	Press Release
Company	Neurogen, Merck & Co
Tags	Central Nervous System, Research Collaboration
Date	January 16, 2004

Branford, CT — January 16, 2004 — Neurogen Corporation (Nasdaq: NRGN) today announced that it has consummated its previously announced alliance with Merck & Co ., Inc. (NYSE: MRK) to discover and develop next-generation drugs for the treatment of pain. The deal received clearance from the Federal Trade Commission under the Hart-Scott-Rodino Act and the companies have now commenced the collaboration. The alliance, announced December 1, 2003, enables Merck , through a subsidiary, and Neurogen to pool drug candidates targeting the vanilloid receptor (VR1 ), a key integrator of pain signals in the nervous system, and combine their ongoing VR1 programs to form a global research and development collaboration.

With consummation of the deal, Neurogen has received $30 million from Merck , including a $15 million up-front license fee payment and a $15 million equity investment in Neurogen common stock. Under the agreement, Merck has purchased 1,783,252 shares of newly issued Neurogen common stock at $8.41 per share, the average market price per share for the 25 trading days preceding regulatory clearance. Merck ‘s new shareholder position represents approximately 9% of Neurogen ‘s 19,873,464 total shares outstanding.

About Neurogen

Neurogen Corporation targets new small molecule drugs to improve the lives of patients suffering from disorders with significant unmet medical need. Neurogen has generated a portfolio of compelling new drug candidates through its Accelerated Intelligent Drug Discovery (AIDD(TM)) system, its expertise in cellular functional assays, and its depth in medicinal chemistry. Neurogen conducts its research and development independently and, when advantageous, collaborates with world-class pharmaceutical companies to obtain additional resources and to access complementary expertise.

////////

n1c(nc(cc1c2ccc(cc2)F)N3CCN(C[C@H]3C)c4ncc(cc4C)C(=O)O)N5CCC[C@H]5C

5-Bromo-1-methyl-1H-imidazole-4-carbonitrile

January 30, 2016 2:51 pm / Leave a comment

Source: 5-Bromo-1-methyl-1H-imidazole-4-carbonitrile

Fresolimumab

January 30, 2016 4:23 am / 1 Comment on Fresolimumab

Fresolimumab
GC 1008, GC1008
UNII-375142VBIA

cas 948564-73-6

Structure

immunoglobulin G4, anti-(human transforming growth factors beta-1, beta-2 (G-TSF or cetermin) and beta-3), human monoclonal GC-1008 γ4 heavy chain (134-215′)-disulfide with human monoclonal GC-1008 κ light chain, dimer (226-226”:229-229”)-bisdisulfide
immunoglobulin G4, anti-(transforming growth factor β) (human monoclonal GC-1008 heavy chain), disulfide with human monoclonal GC-1008 light chain, dimer

For Idiopathic Pulmonary Fibrosis, Focal Segmental Glomerulosclerosis,and Cancer

An anti-TGF-beta antibody in phase I clinical trials (2011) for treatment-resistant primary focal segmental glomerulosclerosis.

A pan-specific, recombinant, fully human monoclonal antibody directed against human transforming growth factor (TGF) -beta 1, 2 and 3 with potential antineoplastic activity. Fresolimumab binds to and inhibits the activity of all isoforms of TGF-beta, which may result in the inhibition of tumor cell growth, angiogenesis, and migration. TGF-beta, a cytokine often over-expressed in various malignancies, may play an important role in promoting the growth, progression, and migration of tumor cells.

Fresolimumab (GC1008) is a human monoclonal antibody^[1] and an immunomodulator. It is intended for the treatment of idiopathic pulmonary fibrosis (IPF), focal segmental glomerulosclerosis, and cancer^[2]^[3] (kidney cancer and melanoma).

It binds to and inhibits all isoforms of the protein transforming growth factor beta (TGF-β).^[2]

History

Fresolimumab was discovered by Cambridge Antibody Technology (CAT) scientists^[4] and was one of a pair of candidate drugs that were identified for the treatment of the fatal condition scleroderma. CAT chose to co-develop the two drugs metelimumab (CAT-192) and fresolimumab with Genzyme. During early development, around 2004, CAT decided to drop development of metelimumab in favour of fresolimumab.^[5]

In February 2011 Sanofi-Aventis agreed to buy Genzyme for US$ 20.1 billion.^[6]

As of June 2011 the drug was being tested in humans (clinical trials) against IPF, renal disease, and cancer.^[7]^[8] On 13 August 2012, Genzyme applied to begin a Phase 2 clinical trial in primary focal segmental glomerulosclerosis^[9] comparing fresolimumab versus placebo.

As of July 2014, Sanofi-Aventis continue to list fresolimumab in their research and development portfolio under Phase II development.^[10]

References

1 WHO Drug Information

2 National Cancer Institute: Fresolimumab

3 Statement On A Nonproprietary Name Adopted By The USAN Council – Fresolimumab
4 Grütter, Christian; Wilkinson, Trevor; Turner, Richard; Podichetty, Sadhana; Finch, Donna; McCourt, Matthew; Loning, Scott; Jermutus, Lutz; Grütter, Markus G. (2008-12-23). “A cytokine-neutralizing antibody as a structural mimetic of 2 receptor interactions”. Proceedings of the National Academy of Sciences 105 (51): 20251–20256. doi:10.1073/pnas.0807200106. ISSN 0027-8424. PMC 2600578. PMID 19073914.
5 http://www.independent.co.uk/news/business/news/cat-may-abandon-skin-drug-after-trial-results-disappoint-569445.html
6 http://www.bbc.co.uk/news/business-12477750
7 http://www.genengnews.com/gen-news-highlights/scientists-trigger-white-fat-to-become-brown-fat-like-to-treat-obesty-and-type-2-diabetes/81245389/
8 Clinicaltrials.gov for Fresolimumab
9 http://clinicaltrials.gov/show/NCT01665391
10 http://en.sanofi.com/rd/rd_portfolio/rd_portfolio.aspx

Fresolimumab
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	TGF beta 1, 2 and 3
Clinical data
Legal status	Investigational
Identifiers
CAS Number	948564-73-6
ATC code	None
ChemSpider	none
KEGG	D09620
Chemical data
Formula	C₆₃₉₂H₉₉₂₆N₁₆₉₈O₂₀₂₆S₄₄
Molar mass	144.4 kDa

////////////

Monoclonal antibodies for the immune system

Immune system (“-l(i[m])-“)

Human (“-limu-“)	immunosuppression: Abrilumab Adalimumab Anifrolumab Atorolimumab Belimumab Brodalumab Carlumab Dupilumab Durvalumab Eldelumab Fresolimumab Golimumab Lerdelimumab Lirilumab Mavrilimumab Metelimumab Morolimumab Namilumab Oxelumab§ Placulumab Sarilumab Sifalimumab Tabalumab Ulocuplumab Varlilumab immune activation: Ipilimumab Nivolumab Pembrolizumab Tremelimumab Urelumab other: Bertilimumab Zanolimumab

Mouse (“-limo-“)	Afelimomab Elsilimomab Faralimomab Gavilimomab Inolimomab Maslimomab Nerelimomab Odulimomab Telimomab aritox Vepalimomab Zolimomab aritox

Chimeric (“-lixi-“)	Basiliximab Clenoliximab Galiximab Gomiliximab Infliximab Keliximab Lumiliximab Priliximab Teneliximab Vapaliximab

Humanized (“-lizu-“)	immunosuppressive: Aselizumab Apolizumab Benralizumab^† Cedelizumab Certolizumab pegol Daclizumab Eculizumab Efalizumab Epratuzumab Erlizumab Etrolizumab Fontolizumab Itolizumab Lampalizumab Ligelizumab Lulizumab pegol Mepolizumab Mogamulizumab Natalizumab Ocrelizumab Omalizumab Ozoralizumab Pascolizumab Pateclizumab Pembrolizumab Pexelizumab Pidilizumab PRO 140^† Reslizumab Rontalizumab Rovelizumab Ruplizumab Quilizumab Samalizumab Siplizumab Talizumab Teplizumab Tocilizumab Toralizumab Tregalizumab Vatelizumab Vedolizumab Visilizumab TGN1412^§ non-immunosuppressive: Ibalizumab^†

Chimeric + humanized (“-lixizu-“)	Otelixizumab

Interleukin (“-k(i[n])-“)

Human (“-kinu-“)	Briakinumab Canakinumab Fezakinumab Fletikumab Guselkumab Secukinumab Sirukumab Tralokinumab Ustekinumab

Humanized (“-kizu-“, “-kinzu-“)	Anrukinzumab Clazakizumab Enokizumab Gevokizumab Ixekizumab Lebrikizumab Olokizumab Perakizumab Tildrakizumab

Inflammatory lesions (“-les-“)

Mouse (“-leso-“)	Besilesomab Fanolesomab^‡ Lemalesomab Sulesomab

^#WHO-EM
^‡Withdrawn from market
Clinical trials:
- ^†Phase III
- ^§Never to phase III

v t e Index of the immune system

Description	Physiology cells autoantigens autoantibodies complement surface antigens IG receptors

Disease	Allergies Immunodeficiency Immunoproliferative immunoglobulin disorders Hypersensitivity and autoimmune disorders Neoplasms and cancer

Treatment	Procedures Drugs antihistamines immunostimulants immunosuppressants monoclonal antibodies

GCC 4401C , GC 2107 , Nokxaban for treating thrombosis

January 29, 2016 4:46 am / Leave a comment

GCC-4401C ( GC-2107), Nokxaban

In phase 1 for treating thrombosis

5-chloro-N-({(5S)-2-oxo-3-[4-(5,6-dihydro-4H-[1,2,4]triazin-1-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide methanesulfonate

5-chloro-N-[[3-[4-(5,6-dihydro-2H-1,2,4-triazin-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]thiophene-2-carboxamide

CB02-0133; GC-2107; GC4401; GCC-2107; GCC-4401; GCC-4401C; I Fxa – LegoChem Biosciences; LCB02-0133; Nokxaban

WO2010002115; LegoChem Bioscience INNOVATOR

	Green Cross Corporation, Legochem Bioscience Ltd.

Green Cross Corporation, Legochem Bioscience Ltd.

DEVELOPER

CAS NO FREE FORM

CAS 1159610-29-3, 159610-29-3, C₁₈ H₁₈ Cl N₅ O₃ S

2-Thiophenecarboxamide, 5-chloro-N-[[(5S)-3-[4-(5,6-dihydro-1,2,4-triazin-1(2H)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-

Molecular Formula: C₁₈H₁₈ClN₅O₃S Molecular Weight: 419.88522 g/mol

METHANE SULFONATE

CAS 1261138-12-8, C₁₈ H₁₈ Cl N₅ O₃ S . C H₄ O₃ S,

2-Thiophenecarboxamide, 5-chloro-N-[[(5S)-3-[4-(5,6-dihydro-1,2,4-triazin-1(2H)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-, methanesulfonate (1:1)

HYDROCHLORIDE

CAS 1261138-08-2., C₁₈ H₁₈ Cl N₅ O₃ S . Cl H, 2-Thiophenecarboxamide, 5-chloro-N-[[(5S)-3-[4-(5,6-dihydro-1,2,4-triazin-1(2H)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-, hydrochloride (1:1)

SUMMARY

09 Jan 2015GC 2107 is available for licensing as of 09 Jan 2015. http://www.greencross.com
01 May 2014Green Cross Corporation completes a phase I trial in Healthy volunteers in USA (NCT01954238)
26 Sep 2013Green Cross initiates enrolment in a phase I trial in Healthy volunteers in USA (NCT01954238)

Used as factor Xa antagonist for treating coronary artery disease, inflammatory disease, myocardial infarction and thrombosis.

Green Cross Corp in collaboration with LegoChem Bioscience, is developing GCC-4401C ( phase I), for treating thrombosis including venous thromboembolism

KDDF-201210-04

Development and Market Objectives

Green Cross Corporation is developing an orally available direct Factor Xa inhibitor, GCC-4401C, which has shown an excellent safety profile during Phase I clinical study. After completion of Phase II and III studies for the prevention of venous thromboembolism (VTE) on hip or knee replacement surgery patients, we will explore additional indications for the treatment of acute coronary syndromes and the prevention of stroke in patients with atrial fibrillation.

Unmet Medical Need & Target Patients

/__DATA/Tasks/2013/9/녹십자1.jpg

GCC-4401C may prove its greatest impact in providing a much-needed and attractive alternative to warfarin in various indications. Prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism in patients undergoing hip or knee arthroplasty, is considered to be a primary unmet medical need. It is the most common cause for rehospitalisation in this patient group. Each year in the United States, between 350,000 and 600,000 people experience a blood clot in the legs or in the lungs. The US and European hip and knee implant markets are the two largest, accounting for nearly 80 percent of total procedures conducted worldwide. The 2005 revenues for hip and knee implants in the US and Europe were $6.5 billion. Demand driven by an aging population and an increasing number of younger patients are contributing to the continuous growth of hip and knee replacement procedures.

Thromboembolism involving arterial or venous circulation is a common cause of morbidity and mortality. As an anticoagulation therapy, heparin and Vitamin K antagonists (VKAs) such as warfarin have been used in clinical settings for more than 50 years, but both are associated with several limitations requiring frequent coagulation monitoring due to unpredictable effects of anticoagulant . Therefore, there is an urgent need for novel, oral agents with a predictable anticoagulant action. The greatest unmet medical need in anticoagulation therapy is to find a replacement for VKAs for long-term therapy, particularly stroke prevention in patients with atrial fibrillation (a heart rhythm disorder). Recently, Factor Xa has emerged as an attractive target for novel anticoagulants and a number of Factor Xa inhibitors are currently under development as oral anticoagulants for long-term use.
A major unmet medical need is for direct FXa inhibitors that are simpler to administer than VKAs, with fewer strokes and less intracranial bleeding compared with warfarin and less bleeding yet similar or better efficacy with a lower-dose regimen. In addition, the availability of simple, fixed-dose, unmonitored therapies should increase the use of direct FXa inhibitor therapy in patients with atrial fibrillation at risk for stroke.

Status

Phase I Clinical Study

To investigate the safety and tolerability of single doses of GCC-4401C in healthy male subjects, a Phase Ia study (GCC-4401C-101) was recently conducted at Quintiles in the United States under the conditions of randomized, double-blind, placebo-controlled, and single ascending dose. Forty eight healthy male subjects were enrolled in 6 cohorts and administered at 6 dose-escalation levels up to 80 mg/subject. GCC-4401C was well-tolerated without any significant adverse events, and was detected in blood plasma dose-proportionally across the dose range of 2.5 mg to 80 mg per patient. The pharmacodynamic variables were also statistically correlated with GCC-4401C plasma concentrations.
We plan to characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple doses of GCC-4401C in healthy male subjects based on the safety margins of the SAD study. An appropriate dose and dosing regimen of oral GCC-4401C from subsequent clinical trials on VTE patients are expected to be identified. The Phase 1b study will be completed with Global CRO in the US in 3Q, 2014.

Intellectual Property

Material patent for GCC-4401C, covering a wide range of chemical structures, was awarded in early 2008 within S. Korea, followed by its production method patent in early 2011. Moreover, patent applications for both material and production method, are in progress in 21 and 5 overseas countries including the US, respectively.
–          KR811865 : Pyrimidinone derivatives or pyridazinone derivatives for inhibition of factor VIIa activity
–          KR109594 : FXa inhibitors with cyclic amidines as P4 subunit, processes for their preparations, and pharmaceutical compositions and derivatives thereof
–          KR898361 : FXa inhibitors with cyclic amidoxime or cyclic amidrazone as P4 subunit, processes for their preparations, and pharmaceutical compositions and derivatives thereof
–          KR1037051 : Method for preparing of (S)-5-chloro-N-((3-(4-(5,6-dihydro-4H-1,2,4-oxadiazin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide derivatives
–          KR1037052 : Method for preparing 5-chloro-N-(((5S)-2-oxo-3-(4-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophen-2-carboxamide derivatives, and their intermediates
–          PCT/KR2010/004420 : Method for preparing (S)-5-chloro-N-((3-(4-(5,6-dihydro-4H-1,2,4-oxadiazin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide derivatives
–          PCT/KR2010/004421 : Method for preparing 5-chloro-N-({(5S)-2-oxo-3-[4-(5,6-dihydro-4H-[1,2,4]triazin-1-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide derivative and intermediate used therein

Competitive Advantages

/__DATA/Tasks/2013/9/녹십자2.jpg

GCC-4401C has been specifically designed for chronic, once-a-day treatment. It has a half-life that supports true, once-daily dosing and a low peak-to-trough drug concentration ratio that minimizes anticoagulant variability. Since GCC-4401C has an excellent aqueous solubility, there has been potential for the development of both po and iv formulations. Data from comparative efficacy studies in animals have also demonstrated the superiority of GCC-4401C against other direct FXa inhibitors with less bleeding effects. From the recent Phase Ia clinical study, GCC-4401C did not show any significant sign of adverse events. PK parameters and PD markers were predictable dose-proportionally across the all dose ranges. GCC-4401C is expected to show excellent safety profiles, less bleeding and less liver toxicity through human clinical studies.

Contact & Company Overview

Company Name :

Green Cross Corporation
Homepage :

http://eng.greencross.com/
Contact Person :

Hyoung Geun Beak, Deputy General Manager, Business
E-mail :

hgbeak@greencross.com
Contact :

+82-31-260-9337

PATENT

WO 2016010178

GREEN CROSS CORPORATION [KR/KR]; 107, Ihyeon-ro 30beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-770 (KR).
LEGOCHEM BIOSCIENCES, INC. [KR/KR]; 8-26, Munpyeongseo-ro, Daedeok-gu, Daejeon 306-220 (KR)

The present invention relates to a novel crystalline form of 5-chloro-N-({(5S)-2-oxo-3-[4-(5,6-dihydro-4H-[1,2,4]triazin-1-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide methanesulfonate and a pharmaceutical composition containing the same. The novel crystalline form of a compound according to the present invention exhibits excellent stability even in high-temperature and humidity environments, and thus can be favorably used to prevent or treat diseases, such as thrombosis, myocardial infarction, atherosclerosis, inflammation, stroke, angina pectoris, restenosis after angioplasty, and thromboembolism.

According to the present invention 5-chloro -N – ({(5 S) -2- oxo-3- [4- (5,6-dihydro the -4H- [1, 2, 4] triazine-1-yl) phenyl] -1, 3-oxazolidin-5-yl} methyl) thiophene-2-mid copy methane sulfonic acid salt (hereinafter referred to as a new crystal form has excellent solubility referred to) in “GCO4401C”, Ko Un and wet environments It is excellent in stability.

Novel crystalline forms of GCC-4401C of the present invention, the organic solvent under reduced pressure crystallization method, a cooling crystallization method or solvent-can be easily obtained by the anti-solvent crystallization process.

Ateumyeo GCC-4401C is used as a reaction raw material can be prepared according to the procedure described in PCT Publication No. W02011 / 005029 No., dissolving the starting compound in an organic solvent the semi-adding a solvent after filtration to determine the resulting mixture was cooled and then dried to give the novel crystalline form can be a compound according to the invention.

PATENT

http://www.google.com/patents/WO2011005029A2?cl=en

5-Chloro-N-( {(5S)-2-oxo-3-[4-(5,6-dihydro-4H-[ 1 ,2,4]triazin- 1-yl)phenyl]-l,3-oxazolidin-5-yl}-methyl)thiophene-2-carboxamide of formula (A) has been known as an inhibitor of blood coagulation factor Xa and used for treating and preventing thrombosis, myocardial infarction, arteriosclerosis, inflammation, stroke, angina pectoris, recurrent stricture after angioplasty, and thromboembolism such as intermittent claudication.

Korea Patent No. 2008-64178, whose application has been filed by the present invetors, discloses a use of the compound as an inhibitor of blood coagulation factor Xa and a preparation method thereof. The preparation method comprises the step of preparing a cyclic amidrazone starting from 4-nitroaniline, as shown in reaction scheme 1 :

Reaction Scheme 1

Specifically, the cyclic amidrazone (A) is prepared by the steps of: preparing the compound (B) using 4-nitroaniline; treating the compound (B) with a t-butoxycarbonyl amine protecting group to prepare the compound (C); introducing a nitroso group into the compound (C) using NaNO₂, followed by reduction using zinc to prepare the compound (D); and treating the compound (D) successively with hydrochloric acid and an ortho-formate.

However, the above preparation method is complicated and gives a low yield of the compound (A) (e.g., a total yield of 9 %), and it also requires the use of a column chromatography purification step, which limits mass production of the cyclic amidrazone. In particular, the step for preparing the compound (D) from the compound (C) is required to use a harmful heavy metal-containg materal such as zinc amalgam which gives an unsatisfactorily low yield, and the isolation step of the compound (D) does not proceed easily.

Reaction Scheme 2

Reaction Scheme 3

Example 1: Preparation of Ethyl formimidate hydrochloride

To a solution of benzoyl chloride (1212 g, 8.62 mol, 1 eq) in anhydrous ether (5.8 L) was added dropwise a solution of formamide (388 g, 8.62 mol, 1 eq) in EtOH (396 g, 8.60 mol, 0.998 eq) at 0 ^°C for lhr. The mixture thus obtained was stirred at 0 ^°C for 30min. The solid was filtered off, washed with ether (3 L) and EA (3 L). The solid was dried under high vacuum.

Yield : 625 g (66%)

Example 1: 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-lH-[l,2,4]triazin-4-yl)phenyl]-l,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide hydrochloride

Step 1: Preparation of 2- [N-(4-nitro-phenyl)-hydrazino]-ethanol

l-Fluoro-4-nitrobenzene (7.1 g, 50 mmol) was dissolved in CH₃CN (70 ml), 2-hydroxyethylhyrazine (purity: 90 %, Aldrich, 5.0 g, 66 mmol) and K₂CO₃ (7.6 g, 55 mmol) were added thereto. The suspension thus obtained was stirred for 4 hrs with reflux. The resulting orange-colored suspension was concentrated under reduced pressure (reflux condenser, 10 torr, 40 ^°C) and ethylacetate (EA, 90 ml) and water (18 ml) were added thereto. The resulting mixture was stirred strongly at r.t. for 10 min. The organic layer was extracted and washed with the saturated brine (10 ml). The resulting solution was cooled to 10 °C and 48 % HBr solution (3.7 ml) was added thereto dropwise with stirring. The pale yellow colored solid thus obtained was filtered off and dried under high vacuum (1 torr, 40 “C) to obtain the title compound as an intermediate.

Yield: 7.1 g (51 %).

TLC : Rf= 0.62 (EA/MeOH/AcOH = 20/1/0.5)

¹H NMR (600 MHz, DMSO-J₆) δ 8.17 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 9.0 Hz, 2H), 3.82 (t, J= 5.4 Hz, 2H), 3.69 (t, J= 5.4 Hz, 2H)

LCMS: 198 (M+H⁺) (C₈H₁₁N₃O₃)

Step 2: Preparation of l-bromo-2-[N-(4-nitro-phenyl)-hydrazino] -ethane

The compound obtained in Step 1 (38.9 g, 0.140 mol) was suspended in anhydrous 1 ,2-dimethoxyethane (585 ml). The resultant suspension was cooled to 0 ^°C and PBr₃ (15.9 ml, 0.168 mol) was added thereto dropwise for 30 min. The mixture thus obtained was stirred at 60 ^°C for 4 hrs. The pale yellow colored solution thus obtained was concentrated under reduced pressure (reflux condenser, 10 torr, 45 ^°C). The resultant residue (oil) was suspended with water (150 ml) and stirred. Aq. sat’d NaHCO₃ solution (150 m) was added to the resultant suspension to be pH 4. The resulting mixture was stirred for 30 min to precipitate the pale yellow colored precipitates. The precipitates were filtered off and washed with water (100 ml). The resulting solid was mixed with water (100 ml), aq. sat’d NaHCO₃ solution (70 ml) and CH₂Cl₂ (500 ml). The resulting mixture was stirred for 10 min and stood to separate organic and aqueous layers. The organic layer was dried over 20 g of MgSO₄ and filtered off. The resulting filterate was concentrated under reduced pressure (reflux condenser, 10 torr, 40 ^°C) to obtain the title compound as a pale yellow solid.

Yield : 31.3 g (86 %)

TLC : Rf= 0.91 (EA/MeOH/AcOH = 20/1/0.5)

¹H NMR (600 MHz, CDCl₃) δ 8.14 (d, J = 10.2 Hz, 2H), 6.92 (d, J= 10.2 Hz, 2H), 4.00 (t, J= 7.2 Hz, 2H), 3.65 (t, J= 7.2 Hz, 2H)

LCMS: 261 (M+H⁺) (C₈H₁₀BrN₃O₂)

Step 3: Preparation of 4-(5,6-dihydro-4H-[l,2,4]triazin-l-yl)-l-nitrobenzene

The compound obtained in Step 2 (13.0 g, 50.0 mmol) was completely dissolved in anhydrous 1,2-dimethoxyethane (200 ml) which is prepared by mixing 1,2-dimethoxyethane (purity: 99 %, Junsei Co. Ltd) with an desired amount of molecular sieve 4A and standing for 5 hrs or more with stirring at times. Ethyl formimidate HCl salt (5.8 g, 52.5 mmol) was added thereto. The suspension thus obtained was stirred at 25 ^°C for 10 min. Anhydrous sodium acetate (NaOAc, 8.6 g, 105 mmol) was added thereto and stirred for 15 hrs with reflux. The orange colored suspension thus obtained was concentrated under reduced pressure (10 torr, 50 “C). The orange colored residue thus obtained was mixed with IN HCl (140 ml), EA (50 ml) and hexane (100 ml), and stirred at r.t for 10 min. A small amount of insoluble suspended solids was remained in aqueous layer and filtered off. The resulting aqueous layer was washed with a mixture of EA (30 ml) and hexane (60 ml). 12 g of sodium carbonate was added to the resulting solution to be pH 8.5. The orange colored solid thus obtained was filtered off under reduced pressure, washed with water (15 ml) and dried under vacuum to obtain the title compound .

Yield : 7.7 g (75 %).

TLC : R/= 0.45 (EA/MeOH/AcOH = 20/1/0.5)

HPLC : R, = 8.65 (Gradient A), purity 91.1%

¹H NMR (400 MHz, DMSO-^₆) δ 8.03 (d, J= 9.6 Hz, 2H), 7.16 (d, J = 9.6 Hz, 2H), 7.12 (br s, IH), 7.01 (d, J= 4.0 Hz, 2H), 3.77 (t, J= 5.2 Hz, 2H), 3.43-3.40 (m, 2H)

LCMS: 207 (M+H⁺) (C₉H₁₀N₄O₂)

Step 4: Preparation of 4-(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yl)-1-nitrobenzene

To the orange colored suspension prepared by suspending the compound obtained in Step 3 (12.4 g, 60 mmol) in tetrahydrofurane (THF, 200 ml), 4-dimethylaminopyridine (DMAP, 0.367 g, 3 mmol) and di-tert-butyl dicarbonate

(BoC₂O, 19.6 g, 90 mmol) were added and stirred with reflux for 1.5 hrs. The yellow colored suspension thus obtained was concentrated under reduced pressure

(reflux condenser, 10 torr, 40 ^°C) to remove the solvent. The resulting yellow colored residue was completely dissolved in CH₂Cl₂ (700 ml) and washed with IN HCl (700 ml). The organic layer was extracted, dried over 25 g of MgSO₄, and concentrated under reduced pressure (condenser, 10 torr, 40 ^°C). The resultant yellow colored residue was dissolved in cyclohexane (250 ml) and stirred strongly at r.t. for 30 min. The resulting mixture was concentrated under reduced pressure to obtain yellow colored solids. The solids were dried (1 torr, 50 ^°C ) to obtain a disried compound.

Yield: 15.6 g (85 %)

TLC : R/= 0.93 (EA/MeOH/AcOH = 20/1/0.5)

¹H NMR (600 MHz, DMSO-J₆) δ 8.14 (d, J= 9.6 Hz, 2H), 7.62 (br s, IH), 7.30 (d, J = 9.6 Hz, 2H), 3.89 (br s, 2H), 3.79 (br s, 2H), 1.50 (s, 9H)

LCMS: 307 (M+H⁺) (C₁₄H₁₈N₄O₄)

Step 5: Preparation of 4-(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yl)aniline

To the yellow colored suspension prepared by suspending the compound obtained in Step 4 (19.9 g; 65 mmol) in methanol (200 ml), 10 % palladium on carbon (4.0 g) was added. The resulting mixture was subjected to vacuum outgassing and stirred at r.t., for 2 hrs in the flask connected with hydrogen bollum. The resulting mixture was filtered through celite 545 under redued pressure to remove the palladium on carbon. The fϊlterate was concentrated under reduced pressure (reflux condenser, 10 torr, 40 °C). The resulting pale brown colored residue was dissolved in isopropylalcohol (140 ml) and refluxed to dissolve completely. The resulting solution was stood at 0 ^°C for 2 hrs to cool, stirred for 30 min and filtered off under redued pressure. The resulting ivory crystalline solid was dried in vacuo to obtain the title compound (15.8 g, 88 %).

TLC : R_f= 0.38 (EA/MeOH/AcOH = 20/1/0.5)

¹H NMR (400 MHz, DMSO-(I₆) δ 7.34 (br s, IH), 6.91 (d, J = 12.0 Hz, 2H), 6.51 (d, J = 12.0 Hz, 2H), 6.64 (br s, 2H), 3.74 (br s, 2H), 3.41 (br s, 2H), 1.48 (s, 9H)

LCMS: 277 (M+H⁺) (C₁₄H₂₀N₄O₂)

Step 6: Preparation of N-(3-(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yI)anilino-(2R)-2-hydroxypropyI)-5-chloro-2-thiophene carboxamide

The compound obtained in Step 5 (19.3 g, 70 mmol) and 5-chloro-N-(((S)-oxiran-2-yl)methyl)thiophene-2-carboxamide (19.1 g, 88 mmol) were suspended in isobutyl alcohol (350 ml) and stirred for 18 hrs with reflux. The dark blue colored solution thus obtained was concentrated under reduced pressure (reflux condenser, 10 torr, 50 °C). To the yellow solid residue thus obrained, ethylacetate (200 ml) was added and the resulting mixture was stirred at r.t. for 30 min and further stirred strongly at 0 ^°C for 30 min. The suspended solid thus obtained was filtered off under reduced pressure and dried in vaccum (1 torr, 50 °C ) to obtain the title compound as ivory crude.

Yield : 25.9 g (75 %)

TLC : R_/= 0.34 (EA/MeOH/AcOH = 20/1/0.5)

¹H NMR of a crude sample (600 MHz, DMSO-</₆) δ 8.62 (t, J = 5.4 Hz, IH), 7.69 (d, J = 3.6 Hz, IH), 7.36 (br s, IH), 7.18 (d, J = 4.2 Hz, IH), 6.95 (d, J = 9.0 Hz, 2H), 6.54 (d, J = 9.0 Hz, 2H), 5.10 (t, J = 6.6 Hz, IH), 5.05 (d, J = 5.4 Hz, IH), 3.81-3.75 (m, 3H), 3.44 (br s, 2H), 3.37-3.34 (m, IH), 3.25-3.21 (m, IH), 3.08-3.04 (m, IH), 2.94-2.89 (m, IH), 1.48 (s, 9H)

LCMS: 494 (M+H⁺) (C₂₂H₂₈ClN₅O₄S)

Step 7: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yl)phenyl]-l,3-oxazolidin-5-yI}-methyl)-2-thiophene carboxamide

The compound obtained in Step 6 (25.2 g, 51 mmol) was completely dissolved in THF (325 ml), and Ll’-carbonyldiimidazole (10.8 g, 66 mmol) and DMAP (0.31 mg, 2.6 mmol) were added thereto. The resulting mixture was stirred with reflux for 18 hrs. The resulting pale yellow colored suspension was cooled to r.t, concentrated under reduced pressure and dried in vacuo (1 torr, 50 ^°C) to obtain the title compound as an ivory solid.

Yield : 23.3 g (88 %)

TLC : R/= 0.75 (EA/MeOH/AcOH = 20/1/0.5)

¹H NMR (400 MHz, DMSO-J₆) δ 8.97 (t, J = 5.4 Hz, IH), 7.69 (d, J= 4.2 Hz, IH), 7.43 (br s, IH), 7.41 (d, J = 9.0 Hz, 2H), 7.20 (d, J = 4.2 Hz, IH), 7.19 (d, J= 9.0 Hz, 2H), 4.82-4.77 (m, IH), 4.12 (t, J= 9.0 Hz, IH), 3.80-3.78 (m, 3H), 3.62 (br s, 2H), 3.59 (t, J= 6.0 Hz, 2H), 1.49 (s, 9H)

LCMS: 520 (M+H⁺) (C₂₃H₂₆ClN₅O₅S)

Step 8: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4H-[l,2,4]triazin-l-yl)phenyl]-l,3-oxazolidin-5-yl}-methyl)-2-thiophene

carboxamide hydrochloride

The compound obtained in Step 7 (16.1 g, 31 mmol) was completely

dissolved in THF (193 ml), 3N HCl (193 ml) was added thereto. The resulting solution was stirred with reflux for 1 hr. The white suspension thus obtained was cooled tq r.t, concentrated under reduced pressure and dried in vacuo (1 torr, 40 ^°C ) to obtain the title compound as a white solid.

Yield : 13.4 g (95 %)

TLC : R/= 0.82 (MC/MeOH/AcOH = 10/1/0.5)

HPLC : R, = 12.39 (Gradient A), purity 99.5%

¹H NMR (600 MHz, OMSO-d₆) δ 12.12 (br s, IH), 10.20 (br s, IH), 9.08

(t, J = 6.0 Hz, IH), 8.60 (d, J = 5.2 Hz, IH), 7.74 (d, J= 4.2 Hz, IH), 7.53 (d, J = 9.0 Hz, 2H), 7.20 (d, J= 4.2 Hz, IH), 7.13 (d, J= 9.0 Hz, 2H), 4.85-4.81 (m, IH),

4.15 (t, J = 8.8 Hz, IH), 3.85 (dd, J = 6.0, 9.2 Hz, IH), 3.66 (t, J = 4.8 Hz, 2H),

3.63-3.56 (m, 2H), 3.19 (br s, 2H)

LCMS: 420 (M+H⁺) (C₁₈H₁₈ClN₅O₃S)

Example 2: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4H-[l,2,4]triazin-l-yI)phenyl]-l,3-oxazolidin-5-yl}-methyI)-2-thiophene

carboxamide

The HCl salt obtained in Example 1 (6.9 g, 15 mmol) was completely dissolved in 33 % methanol aqueous solution (1.1 L) and heated to 50 ^°C while stirring. To the resulting colorlessness solution, 0.6M aq. Na₂CO₃ solution (25 ml) was added and the white suspension thus obtained was stood at 0 ^°C for 0.5 hr to cool. The white solid thus obtained was concentrated under reduced pressure, wished with H₂O (150 ml) and dried in vacuo (1 torr, 40 “C) to obtain the title compound (yield: 5.5 g, 87 %). The title compound was dissolved in methanol (330 ml) and stirred with reflux. The pale yellow colored solution thus obtained was stood at 0 ^°C for 2 hrs to cool. The resulting white solid was concentrated under reduced pressure, washed with methanol (10 ml), and dried in vacuo (1 torr, 40 ^“C) to obtain a crystal of the title compound (yield: 5.0 g, 80 %).

HPLC : R, = 12.37 (Gradient A), purity 99.7 %

¹H NMR (400 MHz, DMSO-^₆) δ 8.97 (t, J = 6.0 Hz, IH), 7.69 (d, J = 4.0 Hz, IH), 7.32 (d, J = 9.2 Hz, 2H), 7.20 (d, J = 4.0 Hz, IH), 7.12 (d, J = 9.2 Hz, 2H), 6.79 (d, J = 4.0 Hz, IH), 6.52 (br s, IH), 4.80-4.75 (m, IH), 4.10 (t, J = 8.8 Hz, IH), 3.77 (dd, J= 6.0, 9.2 Hz, IH), 3.58 (t, J= 5.6 Hz, 2H), 3.33 (s, 4H)

LCMS: 420 (M+H⁺) (C₁₈H₁₈ClN₅O₃S)

Example 3: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4H-[l,2,4]triazin-l-yl)phenyl]-l,3-oxazolidin-5-yI}-methyI)-2-thiophene carboxamide methane sulfonate

To the compound obtained in Example 2 (3.3 g, 7.9 mmol), a mixture solution of MeOH/CH₂Cl₂ (1/4 v/v, 70 ml) was added and stirred with reflux. The pale yellow colored solution thus obtained was cooled to 0 ^°C and methylsulfonic acid (0.56 ml, 8.6 mmol) was added thereto. The resulting mixture was concentrated under reduced pressure (reflux condenser, 10 torr, 40 ^°C) to obtain pale yellow foamy solid. To the resultant solid, absolute ethanol (20 ml) was added and the resulting mixture was stirred with reflux to dissolve solid clearly. The resulting solution was cooled to 0 ^°C to 2 hrs. The resulting white solid was concentrated under reduced pressure, washed with absolute EtOH (5 ml), and dried in vacuo (1 torr, 40 “C) to obtain a crystalline methane sulfonate.

Yield : 3.8 g (93 %)

HPLC : R, – 12.35 (Gradient A), purity 99.8%

¹H NMR (400 MHz, DMSO-CZ₆) δ 11.97 (br s, IH), 10.07 (br s, IH), 8.99

(t, J= 6.0 Hz, IH), 8.59 (U₁ J= 6.0 Hz, IH), 7.70 (d, J= 4.0 Hz, IH), 7.53 (d, J =

9.2 Hz, 2H), 7.20 (d, J= 4.0 Hz, IH), 7.13 (d, J= 9.2 Hz, 2H), 4.86-4.80 (m, IH),

4.16 (t, J = 9.2 Hz, IH), 3.82 (dd, J = 6.0, 9.2 Hz, IH), 3.67 (m, 2H), 3.60 (t, J = 5.6 Hz, 2H), 3.20 (br s, 2H), 2.31 (s, 3H)

LCMS: 420 (M⁺H⁺)(C₁₈H₁₈ClN₅O₃S)

Example 4: (S)-5-chloro-N-((3-(4-(5,6-dihydro-l,2,4-triazin-l(4H)-yl)phenyI)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide methane sulfonate

Step 1: Preparation of (2-[N-(4-nitro-phenyl)-hydrazinyl]-ethanol) hydrobromide

l-Flouro-4-nitrobenzene (428 g, 3.03 mol, Aldrich Fl 1204) was dissolved in CH₃CN (4.3 L), and 2 -hydroxy ethylhyrazine (300 g, 3.94 mol, 1.3 eq, imported from China, >98 %) and K₂CO₃ (461 g, 3.34 mol, 1.1 eq, Aldrich

347825) were added thereto. The mixture thus obtained was stirred at 80 ^°C for

19 hrs. The mixture was cooled to r.t. and evaporated to remove solvent. The residue was dissolved with EA (1.5 L) and H₂O (1 L). The organic layer was extracted and washed with H₂O (500 mL) and brine (200 mL). The extracted

EA layer was cooled to 0 °C and 48 % HBr solution (360 mL, Aldrich 244260) was added thereto dropwise at 0 °C with stirring. The resultant mixture was stirred at 0 ^°C for 1 hr. The solid thus obtained was filtered off and washed with

EA (5 L). The obtained solid was dried under high vacuum to obtain the title compound.

Yield : 531 g (63 %)

TLC : Rf= 0.62 (EA/MeOH/AcOH = 20/1/0.5)

¹H NMR (400 MHz, OMSO-d₆) δ 7.94 (d, J = 9.6 Hz, 2H), 7.12 (br s, 2H), 6.63
5.8 Hz, 2H) LCMS: 198 (M+H⁺) (C₈H₁₁N₃O₃)

Step 2: Preparation of l-bromo-2-[N-(4-nitro-phenyl)-hydrazino]-ethane

The compound obtained in Step 1 (531 g, 1.90 mol) was suspended in

anhydrous 1,2-dimethoxyethane (4.5 L). The resultant suspension was cooled to 0 ^°C and PBr₃ (220 niL, 2.29 mol, 1.2 eq, Aldrich 256536) was added thereto dropwise at 0 ^°C . The mixture thus obtained was warmed up to r.t. and stirred at 6O ⁰C for l5 hrs.

The mixture was cooled to r.t., and filtered off to remove remained insoluble solid. The filter cake thus obtained was washed with 1,2- dimethoxyethane (700 mL) and the filtrate was concentrated in vacuo. The resultant residue was suspended with H₂O (2.5 L), stirred and cooled to 0 ^°C . Aq. 2N NaOH solution (1.7 L) was added thereto at 0^°C to neutralize the suspension mixture (pH 6-7). The solid was filtered off and washed with H₂O (5 L). The filtered solid was air-dried for 5 hrs.

The air-dried solid was dissolved with CH₂Cl₂ (3 L), and aq. sat’d

NaHCO₃ solution (1.5 L) and H₂O (700 mL) were added thereto. The resultant

– mixture was stirred for 15 min and stood to separate organic and aqueous layers. Insoluble solid which was not dissolved in organic layer and H₂O was remained in the mixture. The mixture was filtered off to remove insoluble solid and the filter cake was washed with CH₂Cl₂ (700 mL). The organic layer was extracted, dried over MgSO₄, filtered off, and concentrated in vacuo. The resultant solid was dried under high vacuum to obtain the title compound.

Yield : 383 g (77% : When product was dissolved in CDCl₃ to check the

¹H NMR spectroscopy, insoluble solid was stilled remained in CDCl₃)

TLC : Rf= 0.91 (EA/MeOH/AcOH = 20/1/0.5)

¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J = 9.6 Hz, 2H), 6.92 (d, J = 9.2 Hz, 2H), 4.00 (t, J = 6.6 Hz, 2H), 3.65 (t, J = 6.6 Hz, 2H)

LCMS: 261 (M+H⁺) (C₈H₁₀BrN₃O₂)

Step 3: Preparation of 4-(5,6-dihydro-4H-[l,2,4]triazin-l-yl)-l-nitrobenzene

Ethyl formimidate HCI, NaOAc

1 ,2-dimethoxyethane

The compound obtained in Step 2 (384 g, 1.48 mol) was dissolved in anhydrous 1,2-dimethoxyethane (4 L) and ethyl formimidate HCl salt (322 g, 2.94 mol, 2 eq) was added thereto at r.t. The resultant mixture was stirred at r.t. for 30 min. NaOAc (364 g, 4.44 mol, 3.0 eq, Aldrich 110191) was added to the mixture and the mixture was stirred at 75 ^°C for 15 hrs.

The mixture was cooled to r.t. and evaporated to remove solvent. The resultant residue was suspended in EA (2 L) and 1,2-dimethoxyethane (I L). Aq.

3N HCl solution (2.5 L) was added to the suspension. Insoluble solid was remained in resultant mixture. The solid was filtered off two times to remove insoluble solid. Ether (3 L) was added to the filtrate to separate organic and aqueous layers effectively. Aqueous layer was separated and washed with mixed organic solution (EA (1 L) + Hexane (500 mL)). The combined organic layer should be kept to recover the product.

(The treatment of aqueous layer)

The aqueous layer was cooled to 0 ^°C and aq. 6N NaOH solution (2.2 L) was added thereto slowly to basify the H₂O layer (pH ~ 9). The resultant suspension was stirred at r.t. for 12 hrs. The solid was filtered off and washed with H₂O (3 L) and dried under high vacuum.

(The treatment of combined organic layer)

The combined organic layer was concentrated in vacuo. The resultant residue was acidified with aq. 3N HCl solution (500 mL). Filtration was carried out to remove insoluble solid. The filtrate (H₂O layer) thus obtained was washed with ether (700 mL X 2). The aqueous layer was stirred and cooled to 0 ^°C . Aq. 5N NaOH solution (1 L) was added to the cooled aqueous layer to basify (pH ~9). The mixture thus obtained was stirred at r.t. for 12 hrs. The solid thus obtained was filtered off and washed with H₂O (1.5 L). The solid was dried under high vacuum to obtain the title compound.

Yield : 187 g (62 %)

TLC : Rf= 0.45 (EA/MeOH/AcOH = 20/1/0.5)

¹H NMR (400 MHz, DMSO-</₆) δ 7.99 (d, J = 9.6 Hz, 2H), 7.16 (d, J =

9.6 Hz, 2H), 7.09 (br s, IH), 6.97 (d, J = 3.6 Hz, 2H), 3.73 (t, J = 5.0 Hz, 2H), 3.45-3.46 (m, 2H)

LCMS: 207 (M+H⁺) (C₉H₁₀N₄O₂)

Step 4: Preparation of 4-(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yl)- 1-nitrobenzene

The compound obtained in Step 3 (187g, 0.907 mol) was suspended in anhydrous THF (2.2 L), and BoC₂O (30Og, 1.36 mol, 1.5 eq, Aldrich 205249) and DMAP (6g, 0.045 mol, 0.05 eq, Aldrich 107700) were added thereto. The mixture thus obtained was stirred at 65 ^°C for 5 hrs.

The mixture was cooled to 0 ^°C . MeOH (1.5 L) was added to the mixture at 0 ^°C and stirred at 0 °C for 1 hr. The solid thus obtained was filtered off, washed with MeOH (750 niL) and dried under high vacuum.

Filtrate thus obtained was concentrated in vacuo. MeOH (1 L) was added to the resultant residue with stirring. The mixture thus obtained was stirred at r.t for 12 hrs. Solid thus obtained was filtered off, washed with MeOH (500 mL), and dried under high vacuum to obtain the title compound.

Yield : 182 g (65 %)

TLC : R_f= 0.93 (EA/MeOH/AcOH = 20/1/0.5)

¹H NMR (400 MHz, DMSO-J₆) δ 8.17 (d, J= 9.6 Hz, 2H), 7.57 (br s, IH), 7.19 (d, J= 9.6 Hz, 2H), 3.93-3.86 (m, 2H), 3.83-3.745 (m, 2H), 1.56 (s, 9H)

LCMS: 307 (M+H⁺) (C₁₄H₁₈N₄O₄)

Step 5: Preparation of 4-(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yl)aniline

The compound obtained in Step 4 (134 g, 438 mmol) was suspended in

MeOH (1.3 L) at r.t., and NH₄Cl (12 g, 0.5 eq, Aldrich A4514) and Zn (15 g, 0.5 eq, Aldrich 209988) were added 6 times at intervals of 15 min at r.t. (total amounts Of NH₄Cl = 73 g (1356 mmol, 3.1 eq) and total amounts of Zn = 88 g

(1356 mmol, 3.1 eq))

Temperature of the resultant mixture was risen gradually to 65 ^°C and the mixture was stirred at 65 ^°C for 12 hrs. The mixture was cooled to 40 ^°C and NH₄Cl (12 g, 0.5 eq, Aldrich A4514) and Zn (15 g, 0.5 eq, Aldrich 209988) were added thereto. Temperature of the resultant mixture was risen gradually to 65 ^°C and the mixture was stirred at 65 “C for 1 hr.

The mixture was cooled to r.t. and filtered off through celite pad. The filter cake was washed with MeOH (700 mL) and THF (700 mL) and the filtrate was concentrated. The crude product thus obtained was dried under high vacuum and used without further purification.

Yield : 124 g (quantitative)

TLC : Rf= 0.38 (EA/MeOH/AcOH = 20/1/0.5)

¹H NMR (400 MHz, OMSO-d₆) δ 7.31 (br s, IH), 6.86 (d, J = 12.0 Hz, 2H), 6.48 (d, J = 12.0 Hz, 2H), 4.60 (s, 2H), 3.71 (br s, 2H), 3.38 (br s, 2H), 1.44 (s, 9H)

LCMS: 277 (M+H⁺) (C₁₄H₂₀N₄O₂)

Step 6: Preparation of N-(3-(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yl)anilino-(2R)-2-hydroxypropyl)-5-chloro-2-thiophene carboxamide

The compound obtained in Step 5 (120 g, 435 mmol) and 5-chloro-N-(((S)-oxiran-2-yl)methyl)thiophene-2-carboxamide (123 g, 566 mmol, 1.3 eq, purchased from RStech (Daejeon, Korea) was suspended in absolute EtOH (1450 mL). The mixture thus obtained was stirred at 85 ^°C for 16 hrs. The mixture was cooled to r.t. and evaporated in vacuo to remove solvent. The resultant residue was dried under high vacuum for 18 hrs. The dried solid was suspended in EA (2 L). The suspension thus obtained was stirred at r.t. for 1 hr. The solid thus obtained was filtered off and washed with EA (500 mL) and ether (500 mL). The filtered solid was dried under high vacuum to obtain the title compound.

Aniline (starting material), epoxide, over-reacted by product were contained in crude product.

Yield : 158 g (74 %)

TLC : Rf= 0.34 (EA/MeOH/AcOH = 20/1/0.5)

¹H NMR of a crude sample (400 MHz, DMSO-^₆) δ 8.57 (t, J = 5.4 Hz,

IH), 7.65 (d, J = 3.6 Hz, IH), 7.32 (br s, IH), 7.14 (d, J = 4.2 Hz, IH), 6.90 (d, J

= 9.0 Hz, 2H), 6.51 (d, J = 9.0 Hz, 2H), 5.04 (t, J = 6.6 Hz, IH), 5.00 (d, J = 5.4 Hz, IH), 3.87-3.65 (m, 3H), 3.40 (br s, 2H), 3.37-3.34 (m, IH), 3.25-3.21 (m, IH),

3.17-2.96 (m, IH), 2.94-2.84 (m, IH), 1.44 (s, 9H)

LCMS: 494 (M+H⁺) (C₂₂H₂₈ClN₅O₄S)

Step 7: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yl)phenyl]-l,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide

The compound obtained in Step 6 (158 g, 320 mmol) was suspended in

THF (1000 niL), and 1,1-carbonyldiimidazole (68 g, 416 mmol, 1.3 eq, Aldrich 115533) and DMAP (2 g, 16 mmol, 0.05 eq, Aldrich 107700) were added thereto. The mixture thus obtained was stirred at 75 ^°C for 3 hrs, cooled to r.t, and evaporated in vacuo to remove solvent. The resultant residue was suspended in EtOH (1300 mL). The suspension thus obtained was stirred at 0 ^°C for 1 hr. The solid thus produced was filtered off and washed with cold EtOH (800 mL) and cold MeOH (300 mL). The filtered solid was dried under high vacuum to obtain the title compound.

Yield : 101 g (61 %)

TLC : R/= 0.75 (EA/MeOH/AcOH = 20/1/0.5)

¹H NMR (400 MHz, DMSO-^₆) δ 8.93 (t, J= 5.4 Hz, IH), 7.66 (d, J= 4.2 Hz, IH), 7.43-7.33 (m, 3H),7.29-7.12 (m, 3H), 4.82-4.73 (m, IH), 4.09 (t, J = 9.0 Hz, IH), 3.82-3.70 (m, 3H), 3.65-3.52 (m, 4H), 1.45 (s, 9H)

LCMS: 520 (M+H⁺) (C₂₃H₂₆ClN₅O₅S)

Step 8: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4H-[l,2,4]triazin-l-yl)phenyl]-l,3-oxazolidin-5-yl}-methyl)-2-thiophene

carboxamide hydrochloride

The compound obtained in Step 7 (101 g, 194 mmol) was suspended in aq.

3N HCl solution (1.1 L) and THF (1.1 L), and stirred at 80 “C for 3 hrs. The mixture thus obtained was cooled to r.t. The solid thus produced was filtered off, washed with THF (700 mL) and dried under high vacuum to obtain the title compound.

Yield : 75 g (85 %)

TLC : Rf= 0.82 (MC/MeOH/AcOH = 10/1/0.5)

¹H NMR (400 MHz, DMSO-J₆) δ 12.12 (br s, IH), 10.32 (br s, IH), 9.13

(t, J = 6.0 Hz, IH), 8.57 (d, J= 5.2 Hz, IH), 7.75 (d, J = 4.2 Hz, IH), 7.49 (d, J =

9.0 Hz, 2H), 7.15 (d, J= 4.2 Hz, IH), 7.09 (d, J= 9.0 Hz, 2H), 4.85-4.74 (m, IH), 4.11 (t, J = 8.8 Hz, IH), 3.85 (dd, J = 6.0, 9.2 Hz, IH), 3.62 (t, J = 4.8 Hz, 2H),

3.59-3.49 (m, 2H), 3.15 (br s,2H)

LCMS: 420 (M+H⁺) (C₁₈H₁₈ClN₅O₃)

Example 5: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4H-[l,2,4]triazin-l_^yl)phenyl]-l,3-oxazolidin-5-yl}-methyl)-2-thiophene

carboxamide

The compound obtained in Example 4 (20 g, 43.8 mmol) was suspended in MeOH/H₂O (1/2 wt/wt, 3.2 L) and stirred at 100 ^°C until the compound obtained in Example 4 was dissolved clearly. 0.6M aq. Na₂CO₃ solution (75 mL) was added thereto. The mixture thus obtained was stood at 0 ^°C for 2 hrs. The solid thus produced was filtered off, washed with H₂O (400 mL) and dried

under high vacuum to obtain the title compound.

Yield : 17 g (93 %)

¹H NMR (400 MHz, DMSO-J₆) δ 8.93 (t, J = 6.0 Hz, IH), 7.66 (d, J = 4.0 Hz, IH), 7.29 (d, J = 9.2 Hz, 2H), 7.16 (d, J = 4.0 Hz, IH), 7.08 (d, J = 9.2 Hz, 2H), 6.76 (d, J = 4.0 Hz, IH), 6.48 (br s, IH), 4.78-4.69 (m, IH), 4.07 (t, J = 8.8 Hz, IH), 3.74 (dd, J = 6.0, 9.2 Hz, IH), 3.54 (t, J = 5.6 Hz, 2H), 3.38 (s, 4H)

LCMS: 420 (M+H⁺) (C₁₈H₁₈ClN₅O₃)

Example 6: Preparation of 5-chIoro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4H-[l,2,4]triazin-l-yl)phenyI]-l,3-oxazolidin-5-yl}-methyl)-2-thiophene

carboxamide methane sulfonate

The compound obtained in Example 5 (16.7 g, 39.8 mmol) was suspended in MeOH/CH₂Cl₂ (1/4 v/v, 350 mL) and stirred at 50 ^°C until the compound obtained in Example 5 was dissolved clearly. The mixture thus obtained was cooled to 0 ^°C and methylsulfonic acid (2.9 mL, 43.8 mmol, 1.3 eq, Aldrich 471356) was added thereto at 0 ^°C . The resulting mixture was evaporated in vacuo to remove solvent. The resultant solid was suspended in absolute EtOH (100 mL) and the suspension was stirred at 90 ^°C to dissolve solid clearly. The resulting mixture was cooled to 0 ^°C and stirred at 0 ^°C for 2 hrs. The solid thus produced was filtered off, washed with absolute EtOH (100 mL), and dried under high vacuum to obtain the title compound.

Yield : 18.4 g (89.7 %)

¹H NMR (400 MHz, DMSO-J₆) δ 11.93 (br s, IH), 10.03 (br s, IH), 8.94 (t, J = 6.0 Hz, IH), 8.55 (d, J = 6.0 Hz, IH), 7.66 (d, J = 4.0 Hz, IH), 7.49 (d, J = 9.2 Hz, 2H), 7.16 (d, J = 4.0 Hz, IH), 7.08 (d, J = 9.2 Hz, 2H), 4.93-4.87 (m, IH), 4.10 (t, J = 9.2 Hz, IH), 3.77 (dd, J = 6.0, 9.2 Hz, IH), 3.63 (m, 2H), 3.57 (t, J = 5.6 Hz, 2H), 3.16 (br s, 2H), 2.28 (s, 3H)

LCMS: 420 (M+H⁺) (C₁₈H₁₈ClN₅O₃)

PATENT

WO2010002115

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010002115

[Reaction Scheme 1] [96] A., O

^NCO^NH2 + &J\ – NC NC- boc IPA, reflux O*B£.H. .κ> boc DMAP boc 2

Example 10: Preparation of compound 109

Compound 15a (450 mg, 0.88 mmol) obtained in Manufacturing Example 3 was dissolved in dichloromethane (10 mL), to which HCl (4 M 1,4-dioxane solution) (10 mL) was added, followed by stirring at room temperature for 1 hour. The reactant was concentrated under reduced pressure and dried to give light yellow solid compound (425 mg, 0.88 mmol, 100%). This compound (392 mg, 0.81 mmol) was dissolved in acetic acid (4 mL), to which trimethylorthoformate (2 mL) was added, followed by reflux with stirring. 10 hours later, after solvent was evaporated all, column chromatography (dichlorome thane/me thanol(v/v) 20/1 → 12/1) was performed to give the title compound 109 as a light yellow solid (215 mg, 5.12 mmol, 63 %).

¹H NMR (400 MHz, CDCl₃) δ 7.35 (d, J = 9.2 Hz, 2H), 7.33 (d, J = 4.4 Hz, IH), 7.14 (d, J = 9.2 Hz, 2H), 7.01 (t, J = 6.4 Hz, IH), 6.88 (s, IH), 6.85 (d, J = 4.4 Hz, IH), 4.87-4.79 (m, IH), 4.06 (t, J = 9 Hz, IH), 3.86 (ddd, J = 14.4 ,6, 3 Hz, IH), 3.81 (dd, J = 9, 6.4 Hz, IH), 3.69 (dt, J = 14.4, 6 Hz, IH), 3.62-3.58 (m, 2H), 3.55-3.51 (m, 2H); LCMS: 420 (M+H⁺) to Ci₈H₁₈ClN₅O₃S

REFERENCES

https://clinicaltrials.gov/ct2/show/NCT01954238

SEE EARLIER MOLECULE LCB01-0371…..https://newdrugapprovals.org/2014/03/31/lcb01-0371-new-oxazolidinone-has-improved-activity-against-gram-positive-pathogens/

////////////////phase 1, Green Cross Corp, LegoChem Bioscience, GCC 4401C, thrombosis, venous thromboembolism, GC 2107, CB02-0133, GC-2107, GC4401, GCC-2107, GCC-4401, GCC-4401C, I Fxa – LegoChem Biosciences, LCB02-0133, Nokxaban

O=C(NC[C@H]3CN(c1ccc(cc1)N2CCNC=N2)C(=O)O3)c4ccc(Cl)s4.CS(=O)(=O)O METHANE SULFONATE

O=C(NC[C@H]3CN(c1ccc(cc1)N2CCNC=N2)C(=O)O3)c4ccc(Cl)s4 FREE FORM

C1CN(NC=N1)C2=CC=C(C=C2)N3CC(OC3=O)CNC(=O)C4=CC=C(S4)Cl

Latest Posts

Amogammadex
Amogammadex CAS 1309580-40-2 MF C88H136N8O56S8 MW2458.56 (2R)-2-acetamido-3-[[(1S,3S,5S,6S,8S,10S,11S,13S,15S,16S,18S,20S,21S,23S,25S,26S,28S,30S,31S,33S,35S,36S,38S,40S,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)-10,15,20,25,30,35,40-heptakis[[(2R)-2-acetamido-2-carboxyethyl]sulfanylmethyl]-41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56-hexadecahydroxy-2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39-hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontan-5-yl]methylsulfanyl]propanoic acid L-CYSTEINE, S,S’,S”,S”’,S””,S”””,S”””,S”””’-(6A,6B,6C,6D,6E,6F,6G,6H-OCTADEOXY-.GAMMA.-CYCLODEXTRIN-6A,6B,6C,6D,6E,6F,6G,6H-OCTAYL)OCTAKIS(N-ACETYL-AMOGAMMADEX [INN]CYCLOOCTAKIS-(1->4)-(6-S-((2R)-2-ACETAMIDO-2-CARBOXYETHYL)-6-THIO-.ALPHA.-D-GLUCOPYRANOSYL) cyclooctakis-(1→4)-{6-S-[(2R)-2-acetamido-2-carboxyethyl]-6-thio-α-Dglucopyranosyl}rocuronium and vecuronium reversal agent, L-CYSTEINE, S,S’,S”,S”’,S””,S”””,S”””,S”””’-(6A,6B,6C,6D,6E,6F,6G,6H-OCTADEOXY-.GAMMA.-CYCLODEXTRIN-6A,6B,6C,6D,6E,6F,6G,6H-OCTAYL)OCTAKIS(N-ACETYL-AMOGAMMADEX [INN]CYCLOOCTAKIS-(1->4)-(6-S-((2R)-2-ACETAMIDO-2-CARBOXYETHYL)-6-THIO-.ALPHA.-D-GLUCOPYRANOSYL) Pat WO2012068981 https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012068981&_cid=P21-MJW9RG-10499-1 CD-8 Weigh 23.7…
Alizulatide vixocianine
Alizulatide vixocianine CAS 2924859-51-6 MF C115H145N17O25S, 2,197.55 L-Serine, N-[6-[2-[7-[1,3-dihydro-1,1-dimethyl-3-(4-sulfobutyl)-2H-benz[e]indol-2-ylidene]-1,3,5-heptatrien-1-yl]-1,1-dimethyl-1H-benz[e]indolio]-1-oxohexyl]-L-α-glutamyl-L-α-glutamyl-L-α-aspartyl-3-cyclohexyl-L-alanyl-L-phenylalanyl-D-seryl-D-arginyl-L-tyrosyl-L-leucyl-L-tryptophyl-, inner salt 4-[2-[7-[3-[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2R)-5-carbamimidamido-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxy-2-hydroxyethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-6-oxohexyl]-1,1-dimethylbenzo[e]indol-3-ium-2-yl]hepta-2,4,6-trienylidene]-1,1-dimethylbenzo[e]indol-3-yl]butane-1-sulfonate diagnostic imaging agent, 8M3Q8XZ6MJ Alizulatide vixocianine is a polypeptide that can be discovered…
Aleniglipron
Aleniglipron CAS 2685823-26-9 MF C49H55FN9O6P MW916.0 g/mol 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-diethylphosphoryl-3-(methylamino)phenyl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one glucagon-like peptide 1 (GLP-1) receptor agonist, GSBR-1290, GSBR 1290, Z6XCL6R9SX Aleniglipron (development code GSBR-1290) is a small-molecule GLP-1 agonist developed by Structure Therapeutics.[1] It…
Limnetrelvir
Limnetrelvir CAS 2923500-04-1 MF C27H23F4N5O4 MW 557.50 N-[(3R)-1-[4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl]pyrrolidin-3-yl]-8-fluoro-2-oxo-1H-quinoline-4-carboxamide N-{(3R)-1-[4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl]pyrrolidin-3-yl}-8-fluoro-2-oxo1,2-dihydroquinoline-4-carboxamideantiviral, ABBV-903, ABBV 903, 4TPS988XGG Limnetrelvir (ABBV-903) is a MPro inhibitor. Limnetrelvir could be used in antiviral research. SYN https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=4D458E543A941751578F87216FA39801.wapp1nA?docId=WO2024081351&_cid=P10-MJQJMM-46773-1#detailMainForm:MyTabViewId:PCTDESCRIPTION Example…
Aficamten
Aficamten C18H19N5O2, 337.4 g/mol FDA 2025, APPROVALS 2025, Myqorzo, 12/19/2025, To treat symptomatic obstructive hypertrophic cardiomyopathy CK-3773274, B1I77MH6K1, BAY-3723113; CK 3773274; CK 274; MYQORZO N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]-1-methylpyrazole-4-carboxamide Aficamten,…
Zoliflodacin
Zoliflodacin MF C22H22FN5O7 MW 487.4 g/mol FDA 2025, APPROVALS 2025, 12/12/2025, Nuzolvence (4′R,6′S,7′S)-17′-fluoro-4′,6′-dimethyl-13′-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]spiro[1,3-diazinane-5,8′-5,15-dioxa-2,14-diazatetracyclo[8.7.0.02,7.012,16]heptadeca-1(17),10,12(16),13-tetraene]-2,4,6-trione Spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione, 11-fluoro-1,2,4,4a-tetrahydro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-3-oxazolidinyl]-, (2R,4S,4aS)- (2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione To treat uncomplicated urogenital gonorrhea due to Neisseria gonorrhoeae…
Iscartrelvir
Iscartrelvir CAS 2921711-74-0 MF 2921711-74-0, 526.4 g/mol N-{(1S,2R)-2-[4-bromo-2-(methylcarbamoyl)-6-nitroanilino]cyclohexyl}isoquinoline-4-carboxamideantiviral, WU-04, WU 04, W2LTV65R5E Iscartrelvir is an investigational new drug developed by the Westlake University for the treatment of COVID-19. It targets the SARS-CoV-2 3CL…
Zoracopan
Zoracopan CAS 2243483-63-6 MF C31H31BrN6O3 MW 615.52 2-Azabicyclo[3.1.0]hexane-3-carboxamide, 2-[2-[3-acetyl-7-methyl-5-(2-methyl-5-pyrimidinyl)-1H-indol-1-yl]acetyl]-N-(6-bromo-3-methyl-2-pyridinyl)-5-methyl-, (1R,3S,5R)- (1R,3S,5R)-2-{[3-acetyl-7-methyl-5-(2-methylpyrimidin5-yl)-1H-indol-1-yl]acetyl}-N-(6-bromo-3-methylpyridin2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamidecomplement factor D inhibitor, ALXN-2080, ALXN 2080, E7799Y8LXY Zoracopan is a selective complement factor D (CFD) inhibitor.…
Zopocianine
Zopocianine CAS 2206660-94-6, NA SALT 2206660-95-7 MF C74H93N7O27S4, 1,640.83 L-Tyrosine, N-[[[(1S)-1,3-dicarboxypropyl]amino]carbonyl]-L-g-glutamyl-3-[2-(2-aminoethoxy)ethoxy]propanoyl-L-phenylalanyl-O-[6-[2-[1,3-dihydro-3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-2H-indol-2-ylidene]ethylidene]-2-[2-[3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-3H-indolium-2-yl]ethenyl]-1-cyclohexen-1-yl]-, inner salt N-{[(1S)-1,3-dicarboxypropyl]carbamoyl}-L-γ-glutamyl3-[2-(2-aminoethoxy)ethoxy]propanoyl-L-phenylalanylO-[(6Ξ)-2-{(1Ξ)-2-[3,3-dimethyl-1-(4-sulfobutyl)-5-sulfonato-3H-indol-1-ium-2-yl]ethen-1-yl}-6-{(2Ξ)-2-[3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-1,3-dihydro-2Hindol-2-ylidene]ethylidene}cyclohex-1-en-1-yl]-Ltyrosinediagnostic imaging agent, UD9V5S9M7A, OTL 0078, OTL 78 AS ON OCT2025 4.511…
Zomiradomide
Zomiradomide CAS 2655656-99-6 MF C45H48F3N7O6S MW871.97 antineoplastic, IRAK degrader-1, AQ5UXV5646 Zomiradomide is an orally active PROTAC degrader for IRAK4 (DC50=6 nM), thereby inhibiting the NF-κB signaling pathway. Zomiradomide acts also as…

DISCLAIMER

I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP

Blog at WordPress.com.

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel
	VÍDEOS – A Pfizer ac… on Temanogrel
	Pfizer Bought Arena… on Temanogrel
	Pfizer va profita de… on Temanogrel
	Pfizer to Cash In on… on Temanogrel
	Pfizer tocmai a achi… on Temanogrel
	Pfizer just purchase… on Temanogrel
	Pfizer just purchase… on Temanogrel
	Tanya A on Dasotraline, ダソトラリン
	Julia Chernus on RIDINILAZOLE
	Adv.Siji Antony Kera… on Myself Anthony Crasto up for g…

SEARCH THIS BLOG

FLAGS AND HITS

Meta

Pages

Archives

Categories

MYSELF

Follow Blog via Email

Verified Services

Recent Posts

SEARCH THIS BLOG

Share this:

Share this:

Share this:

(R)-4-((4-(((4-(Tetrahydrofuran-3-yloxy)-1,2-benzisoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol

Two Routes to 4-Fluorobenzisoxazol-3-one in the Synthesis of a 5-HT4Partial Agonist

Share this:

Share this:

Share this:

Development of a Multikilogram Scale Synthesis of a TRPV1 Antagonist

Abstract

Neurogen and Merck Agreement for Next-Generation Pain Drugs Consummated

Share this:

Share this:

History

References

Share this:

PATENT

Share this:

Post navigation

SEARCH THIS BLOG

DR ANTHONY MELVIN CRASTO

Meta

Follow Blog via Email

ORGANIC SPECTROSCOPY

Latest Posts

Pages

feedjit

Recent Comments

DISCLAIMER

SEARCH THIS BLOG

SEARCH THIS BLOG

FLAGS AND HITS

Follow Blog via Email

Two Routes to 4-Fluorobenzisoxazol-3-one in the Synthesis of a 5-HT₄Partial Agonist