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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

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 GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 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, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, 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 30 PLUS year tenure till date June 2021, 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 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 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 33 lakh plus views on New Drug Approvals Blog in 233 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

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Meglimin hydrochloride


Imeglimin hydrochloride (JAN).png
Imeglimin.svg

Meglimin hydrochloride

Twymeeg

Formula C6H13N5. HCl
CAS 775351-61-6 (HCl). , C6H14ClN5 191.66CAS 775351-65-0, FREEFORM 155.20
Mol weight 191.6619

AntidiabeticAPPROVED PMDA JAPAN2021/6/23, イメグリミン塩酸塩

(4R)-6-N,6-N,4-trimethyl-1,4-dihydro-1,3,5-triazine-2,6-diamine

DB12509

NCGC00378621-02

HY-14771

Q6003719

UNII-UU226QGU97

UU226QGU97

1,3,5-Triazine-2,4-diamine,1,6-dihydro-N,N,6-trimethyl-,(+)-(9CI)

(4R)-6-N,6-N,4-trimethyl-1,4-dihydro-1,3,5-triazine-2,6-diamine

Imeglimin [INN]

Emd 387008 (R-imeglimin) HCl

EMD-387008

Imeglimin is an experimental drug being developed as an oral anti-diabetic.[1][2] It is an oxidative phosphorylation blocker that acts to inhibit hepatic gluconeogenesis, increase muscle glucose uptake, and restore normal insulin secretion. It will be the first of a new class of anti-diabetic if it is approved.

A review of phenformin, metformin, and imeglimin - Yendapally - 2020 - Drug Development Research - Wiley Online Library
A review of phenformin, metformin, and imeglimin - Yendapally - 2020 - Drug Development Research - Wiley Online Library

PATENT

https://patents.google.com/patent/WO2012072663A1/enEXAMPLESExample 1 : Synthesis and isolation of (+)-2-amino-3,6-dihydro-4-dimethylamino-6- methyl-l,3,5-triazine hydrochloride by the process according to the invention

Preliminary step: Synthesis of racemic 2-amino-3,6-dihydro-4-dimethylamino- 6-methyl-l,3,5-triazine hydrochloride:

Figure imgf000013_0001

Metformin hydrochloride is suspended in 4 volumes of isobutanol. Acetaldehyde diethylacetal (1.2 eq.) and para-toluenesulfonic acid (PTSA) (0.05 eq) are added and the resulting suspension is heated to reflux until a clear solution is obtained. Then 2 volumes of the solvent are removed via distillation and the resulting suspension is cooled to 20°C. The formed crystals are isolated on a filter dryer and washed with isobutanol (0.55 volumes). Drying is not necessary and the wet product can be directly used for the next step.Acetaldehyde diethylacetal can be replaced with 2,4,6-trimethyl-l,3,5-trioxane (paraldehyde).- Steps 1 and 2: formation of the diastereoisomeric salt and isolation of the desired diastereoisomer

Figure imgf000013_0002

Racemic 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine hydrochloride wet with isobutanol (obtained as crude product from preliminary step without drying) and L-(+)-Tartaric acid (1 eq.) are dissolved in 2.2 volumes of methanol at 20-40°C. The obtained clear solution is filtered and then 1 equivalent of triethylamine (TEA) is added while keeping the temperature below 30°C. The suspension is heated to reflux, stirred at that temperature for 10 minutes and then cooled down to 55°C. The temperature is maintained at 55°C for 2 hours and the suspension is then cooled to 5- 10°C. After additional stirring for 2 hours at 5-10°C the white crystals are isolated on a filter dryer, washed with methanol (2 x 0.5 Vol) and dried under vacuum at 50°C. The yield after drying is typically in the range of 40-45%

– Steps 3 and 4: transformation of the isolated diastereoisomer of the tartrate salt into the hydrochloride salt and recovery of the salt

Figure imgf000014_0001

γ ethanol HN^NH(+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt is suspended in 2 volumes of ethanol and 1.02 equivalents of HCl-gas are added under vacuum (-500 mbar). The suspension is heated to reflux under atmospheric pressure (N2) and 5% of the solvent is removed via distillation. Subsequent filtration of the clear colourless solution into a second reactor is followed by a cooling crystallization, the temperature is lowered to 2°C. The obtained suspension is stirred at 2°C for 3 hours and afterwards the white crystals are isolated with a horizontal centrifuge. The crystal cake is washed with ethanol and dried under vacuum at 40°C. The typical yield is 50-55% and the mother liquors can be used for the recovery of about 25-30%) of (+)-2-amino- 3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate.Example 2: Modification of the solvent of steps 3 and 4

– Steps 3 and 4: transformation of the isolated diastereoisomer of the tartrate salt into the hydrochloride salt and recovery of the salt

Figure imgf000014_0002

HN^NH acetone HN^NH(+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt synthesized according to steps 1 and 2 of example 1 is suspended in 1 volume (based on total amount of (+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt) of acetone at 20°C. To this suspension 1.01 equivalents of 37% Hydrochloric acid are added. The suspension is heated to reflux under atmospheric pressure (N2) and water is added until a clear solution is obtained. 1.5 vol of acetone are added at reflux temperature. The compound starts crystallising and the obtained suspension is kept at reflux for 2 hours followed by a cooling crystallization to 0°C. The obtained suspension is stirred at 0°C for 2 hours and the white crystals are isolated by centrifugation. The crystal cake is washed with isopropanol and dried under vacuum at 40°C in a continuous drying oven.

References

  1. ^ Vuylsteke, V; Chastain, L. M; Maggu, G. A; Brown, C (2015). “Imeglimin: A Potential New Multi-Target Drug for Type 2 Diabetes”Drugs in R&D15 (3): 227–232. doi:10.1007/s40268-015-0099-3PMC 4561051PMID 26254210.
  2. ^ Dubourg, J; Fouqueray, P; Thang, C; Grouin, JM; Ueki, K (April 2021). “Efficacy and Safety of Imeglimin Monotherapy Versus Placebo in Japanese Patients With Type 2 Diabetes (TIMES 1): A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 3 Trial”Diabetes Care44 (4): 952–959. doi:10.2337/dc20-0763PMID 33574125.
 
Names
Preferred IUPAC name(2S)-N6,N6,2-Trimethyl-1,2-dihydro-1,3,5-triazine-4,6-diamine
Identifiers
CAS Number 775351-65-0
3D model (JSmol) Interactive image
ChemSpider 26232690
PubChem CID 24812808
UNII UU226QGU97
CompTox Dashboard (EPA) DTXSID50228237 
showInChI
showSMILES
Properties
Chemical formula C6H13N5
Molar mass 155.205 g·mol−1
Pharmacology
ATC code None
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

/////////Imeglimin hydrochloride, Twymeeg, JAPAN 2021, APPROVALS 2021, Antidiabetic, イメグリミン塩酸塩, ATI DIABETES, DIABETES, Imeglimin

CC1N=C(NC(=N1)N(C)C)N.Cl

wdt-30

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