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Peficitinib hydrobromide, ペフィシチニブ臭化水素酸塩

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Structure of PEFICITINIB HYDROBROMIDE

img

ChemSpider 2D Image | PEFICITINIB HYDROBROMIDE | C18H23BrN4O2

Peficitinib hydrobromide

ペフィシチニブ臭化水素酸塩

ASP015K,

Rheumatoid Arthritis

1H-Pyrrolo(2,3-b)pyridine-5-carboxamide, 4-((5-hydroxytricyclo(3.3.1.13,7)dec-2-yl)amino)-, hydrobromide (1:1), stereoisomer

4-{[(1R,2s,3S,5r)-5-Hydroxyadamantan-2-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrobromide (1:1)

1H-Pyrrolo[2,3-b]pyridine-5-carboxamide, 4-[[(1R,3S)-5-hydroxytricyclo[3.3.1.13,7]dec-2-yl]amino]-, hydrobromide (1:1)

U55XHZ5X6P

Formula
C18H22N4O2. HBr
CAS
1353219-05-2 HBR
944118-01-8 BASE
Mol weight
407.3048

PMDA, 2019/3/26 JAPAN APPROVED, Smyraf

Image result for Peficitinib hydrobromide

Peficitinib hydrobromide is used in the treatment of Psoriasis and Rheumatoid Arthritis

Peficitinib (formerly known as ASP015K) is a pyrrolo[2,3-b]pyridine derivative orally administered once-daily JAK inhibitor in development for the treatment of Rheumatoid Arthritis. In preclinical studied Peficitinib inhibited JAK1 and JAK3 with IC50 of 3.9 and 0.7 nM, respectively. Peficitinib also inhibited IL-2-dependent T cell proliferation in vitro and STAT5 phosphorylation in vitro and ex vivo. Furthermore, Peficitinib dose-dependently suppressed bone destruction and paw swelling in an adjuvant-induced arthritis model in rats via prophylactic or therapeutic oral dosing regimens.In clinical trials, Peficitinib treatment prescribed at 50, 100 and 150 mg amounts each showed statistically significantly higher ACR20 response rates compared to the placebo and response rates increased up to the 150 mg dosage. Adverse events included neutropenia, headache, and abdominal pain. The treatment-emergent adverse events occurring more frequently in the Peficitinib group compared with the placebo group included diarrhea, nasopharyngitis, and increased serum creatine phosphokinase activity. No cases of serious infections were reported. Herpes zoster occurred in four patients (two each in the peficitinib 25 and 100 mg cohorts). The authors concluded that treatment with peficitinib as monotherapy for 12 weeks in Japanese patients with moderate to severe RA is efficacious and showed an acceptable safety profile.

SYN

CLIP

Bioorganic & Medicinal Chemistry

Volume 26, Issue 18, 1 October 2018, Pages 4971-4983

Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor

Abstract

Janus kinases (JAKs) are considered promising targets for the treatment of autoimmune diseases including rheumatoid arthritis (RA) due to their important role in multiple cytokine receptor signaling pathways. Recently, several JAK inhibitors have been developed for the treatment of RA. Here, we describe the identification of the novel orally bioavailable JAK inhibitor 18, peficitinib (also known as ASP015K), which showed moderate selectivity for JAK3 over JAK1, JAK2, and TYK2 in enzyme assaysChemical modification at the C4-position of lead compound 5 led to a large increase in JAK inhibitory activity and metabolic stability in liver microsomes. Furthermore, we determined the crystal structures of JAK1, JAK2, JAK3, and TYK2 in a complex with peficitinib, and revealed that the 1H-pyrrolo[2,3–b]pyridine-5-carboxamide scaffold of peficitinib forms triple hydrogen bonds with the hinge region. Interestingly, the binding modes of peficitinib in the ATP-binding pockets differed among JAK1, JAK2, JAK3, and TYK2. WaterMap analysis of the crystal structures suggests that unfavorable water molecules are the likely reason for the difference in orientation of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold to the hinge region among JAKs.

Image result for Peficitinib hydrobromide

Image result for Peficitinib hydrobromide

Image result for Peficitinib hydrobromide

PATENT

WO 2011162300

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011162300&tab=FULLTEXT&queryString=%28PA%2FAstellas%29+&recNum=126&maxRec=386

Diseases that have good JAK3 inhibitory activity and are caused by undesired cytokine signaling (eg rejection in living transplantation, rheumatism, psoriasis, autoimmune diseases, asthma, atopic dermatitis, Alzheimer’s disease, atherosclerosis etc. Patent Document 1 discloses fused heterocyclic compounds and salts thereof which are useful as therapeutic agents and / or prophylactic agents for diseases (eg, cancer, leukemia, etc.) caused by abnormal cytokine signaling. Among them, 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo represented by the following formula (I) disclosed in the example compound Ex121 [2,3-b] pyridine-5-carboxamide exhibits good activity, and is particularly a compound expected as a therapeutic agent for suppressing rejection during organ / tissue transplantation, rheumatism, psoriasis and the like.
[Chemical formula 1]
 The solid stability of a compound which has become a drug development candidate is an important factor both in industrial operation and in maintaining quality. In the stability of the drug substance itself, it is necessary to evaluate the stability of the quality necessary to maintain the efficacy and safety of the drug, and to obtain the information necessary for setting the storage method and the shelf life of the drug. For this reason, the stability test is considered to be one of the most important tests in the manufacture of pharmaceuticals (Heat measurement, 2004, 31 (2), pp. 80-86).
 Patent Document 1 discloses the free form of the compound of the formula (I) but does not disclose as a crystal. There is a need for a drug substance which is more suitable for formulation, and is physically and chemically stable from the viewpoint of quality assurance.
Example 1
(Production Method of Hydrobromide Salt Form B 45)
(In the Case of Addition of Seed Crystals )
After nitrogen substitution, the reaction vessel was charged with 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy- 2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide (145.0 kg), water (377 L), EtOH (1508 L), 48% hydrobromic acid (74.9 kg) It charged sequentially at room temperature and started stirring. 48% hydrobromic acid was added, taking care that the pH was in the range of 1.5 to 1.9. The reaction mixture was heated and stirred until the internal temperature reached 70 ° C. or higher. After confirming that the solution was completely dissolved, the solution was stirred for 5 minutes or more, and the solution was subjected to clear filtration at an internal temperature of 70 ° C. or higher, and the pot and line were washed with warm EtOH (290 L). At an internal temperature of about 50 ° C., 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide odor Hydrochloric acid salt seed crystals (B45, 145 g) were added, and the mixture was ripened and stirred overnight at an internal temperature of 40 to 50 ° C. Subsequently, the mixture was cooled to an internal temperature of 20 to 30 ° C. over 1 hour or more, and the mixture was aged and stirred at the same temperature for 1 hour or more. At an internal temperature of 20 to 30 ° C., EtOAc (4350 L) was added dropwise over 1 hour, and the mixture was aged and stirred overnight at the same temperature. The precipitated crystals were filtered. The wet crystals were washed with a solution of EtOH / EtOAc (145 L / 290 L). The wet crystals are dried under reduced pressure at an external temperature of 40 ° C. overnight under reduced pressure to give 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3 -b] Pyridine-5-carboxamide hydrobromide crystal (B45, 161 kg) was obtained.

[0037]
(Another method of producing hydrobromide salt B45 type crystal)
(In the case of no addition of seed crystals) After
sufficiently drying the reaction vessel and replacing with nitrogen, water (585 L) is charged and subsequently 4- {[ (1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide (225 kg), EtOH (2250 L) was charged Stirring was started. The internal temperature was adjusted to 25 ° C., and 48% hydrobromic acid (127.8 kg) was charged at the same temperature, and the vessel and kettle wall were washed with EtOH (90 L). After the completion of the charging, it was confirmed that the reaction solution had been dissolved, the pH was measured, and the pH was confirmed to be in the range of 1.5 to 1.9. When the pH was out of the range, the pH was adjusted to a predetermined pH using 48% hydrobromic acid (48% hydrobromic acid: about 11.6 kg). The temperature was raised until the internal temperature reached 70 ° C., and after confirmation of dissolution, the mixture was stirred for 5 minutes or more. The solution was subjected to clear filtration while maintaining the internal temperature at 60 ° C. or higher, and washed through a filter from a dissolution vessel with warm EtOH (450 L) preheated to 50 ° C. or higher. The clarified filtrate was gradually cooled to an internal temperature of 45 ° C., and filtered EtOAc (6750 L) was added dropwise over 6 hours at an internal temperature of 45 ° C. After the dropping was completed, the mixture was stirred at an internal temperature of 45 ° C. for 10 hours or more. Subsequently, it was cooled to an internal temperature of 25 ° C. using a follow-up temperature control cooler, and stirred at an internal temperature of 25 ° C. for 3 hours. The predetermined supernatant concentration and the crystal form of the precipitated crystals were confirmed and filtered. A mixed solvent of EtOH / EtOAc (225 L / 450 L) was prepared and cake washed using this mixed solvent. The obtained wet crystals are dried under reduced pressure at an external temperature of 40 ° C. for 10 hours or more, and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [ 2,3-b] pyridine-5-carboxamido hydrobromide crystal (B45, 250 kg) was obtained.

[0038]
1 H-NMR (600 MHz, d 6 -DMSO) δ: 1.49 (2 H, m), 1. 68 (2 H, m), 1.71 (2 H, m), 1. 80 (2 H, m), 1. 91 (2 H, m), 2.10 (1H, m), 2.20 (2 H, m), 3. 70-4.00 (1 H, brs), 4. 28 (1 H, m), 6. 66 (1 H, m), 7. 39 (1 H, m), 7. 75 (1 H, brs), 8. 38 (1 H, brs), 8.5 5 (1 H, s), 11. 17 (1 H, d, 7.8 Hz), 12.5 (1 H, brs), 14. 17 (1 H, brs)
Elemental analysis: theoretical value: C 53.08%, H 5.69% , N 13.76%, O 7.86% , Br 19.62%;
Found:. C 53.02%, H 5.74 %, N 13.73%, Br 19.42%
molecular composition: C 18 H 22 N 4 O . HBr
MS: 327.0 (M From the result of + H) +
elemental analysis, 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5 The carboxamido hydrobromide was a monohydrobromide.

[0039]
Example 2
(hydrobromide A87 crystal)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] Pyridine-5-carboxamide (6.0 g) was charged in EtOH / water (57.6 mL / 14.4 mL). At 50-60 ° C., 48% hydrobromic acid was added, stirred for 15 minutes more, and washed with EtOH (18 mL). At 45 ° C.-55 ° C. EtOAc (180 mL) was added dropwise over 30 minutes. Crystals were precipitated upon stirring at 15 ° C to 25 ° C. The crystals were collected by filtration and washed with a mixed solvent of EtOH / EtOAc (6 mL / 12 mL). The crystals are dried under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide odor Seed crystals of hydrofluoride (Form A87, 6.11 g) were obtained.
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide (3.0 g), EtOH (24 mL), water (6 mL), and 48% hydrobromic acid (1.55 g) were charged sequentially at room temperature. After charging, the mixture was heated to an internal temperature of 60 ° C. or higher and stirred. After confirming that the solution was completely in solution, the solution was subjected to clear filtration at an internal temperature of 60 ° C. or higher, and washed with warm EtOH (9 mL). EtOH (21 mL) is added dropwise at an internal temperature of 70 ° C. or higher, and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H at an internal temperature of 70 ° C. Seed crystals (A87, 30 mg) of pyrrolo [2,3-b] pyridine-5-carboxamide hydrobromide were added, and the mixture was ripened and stirred overnight at an internal temperature of 65 to 70 ° C. Subsequently, it was cooled to an internal temperature of 20 to 30 ° C., and ripening stirring was carried out at the same temperature overnight. At an internal temperature of 20 to 30 ° C., EtOAc (90 mL) was added dropwise over 1 hour, and the mixture was aged and stirred at the same temperature for 1 hour or more. The precipitated crystals were collected by filtration. The wet crystals were washed with a solution of EtOH / EtOAc (3 mL / 12 mL). The wet crystals are dried overnight under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide Hydrobromide crystal (Form A87, 3.09 g) was obtained.

[0040]
Example 3
(hydrobromide A61 crystal)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] Pyridine-5-carboxamide (5.0 g), EtOH (48 mL), water (12 mL), and 48% hydrobromic acid (2.58 g) were charged sequentially at room temperature. After charging, the mixture was heated to an internal temperature of 70 ° C. and stirred. After confirming complete dissolution, the solution was clarified by filtration at an internal temperature of 70 ° C., and washed with warm EtOH (15 mL). The internal temperature was cooled to 50 to 60 ° C., and EtOAc (150 mL) was added dropwise over 1 hour at the same temperature. After the addition was completed, the solution was gradually cooled to 20 to 30 ° C., and the mixture was aged and stirred at the same temperature for 1 hour or more. The precipitated crystals were collected by filtration. The wet crystals were washed with a solution of EtOH / EtOAc (5 mL / 10 mL). The wet crystals are dried overnight under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide Hydrobromide crystal (Form A61, 5.19 g) was obtained.

[0041]
Example 4
(hydrobromide A36 type crystal)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] To a suspension of pyridine-5-carboxamide (500 mg) in EtOAc, 48% hydrobromic acid (258 μL) was added, and the mixture was stirred with heating under reflux for 1 hour, and further allowed to cool to room temperature. The precipitated crystals were collected by filtration and washed with EtOAc. The resulting crystals are dried at 60 ° C. under reduced pressure to give 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-]. b] Pyridine-5-carboxamide monohydrobromide crystal (Form A36, 625 mg) was obtained.

[0042]
Example 5
(B11-type crystal of hydrobromide monohydrate)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2 , 3-b] Pyridine-5-carboxamide (5.0 g), EtOH (48 mL), water (12 mL), 48% hydrobromic acid (2.58 g) were sequentially charged at room temperature. After charging, the mixture was heated to an internal temperature of 70 ° C. or higher and stirred. After confirming that the solution had completely dissolved, the solution was subjected to clear filtration at an internal temperature of 70 ° C. or higher, and washed with warm EtOH (15 mL). 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide odor at an internal temperature of about 35 ° C. Hydrochloric acid salt seed crystals (A87, 49.0 mg) were added, and the mixture was aged with an internal temperature of 30 to 40 ° C. for 4 hours. Subsequently, the mixture was cooled to an internal temperature of 20 to 30 ° C., and aged and stirred overnight at the same temperature. At an internal temperature of 20-25 ° C., EtOAc (150 mL) was added dropwise over 1 hour, and the mixture was aged and stirred at the same temperature for 30 minutes or longer. The precipitated crystals were collected by filtration. The wet crystals were washed with a solution of EtOH / EtOAc (5 mL / 10 mL). The wet crystals are dried overnight under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide Hydrobromide monohydrate crystal (Form B11, 5.24 g) was obtained.

[0043]
Example 6
(B21-type crystal of hydrobromide dihydrate)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2 , 3-b] Pyridine-5-carboxamide (5.0 g), EtOH (18 mL), water (12 mL), 48% hydrobromic acid (2.58 g) were sequentially charged at room temperature. After charging, the mixture was heated to an internal temperature of 60 ° C. or higher and stirred. After confirming that the solution was completely dissolved, the solution was subjected to clear filtration at an internal temperature of 60 ° C. or higher, and washed with warm EtOH (10 mL). The mixture was cooled to an internal temperature of about 45 to 50 ° C. and aged for 2 hours while stirring. Subsequently, the reaction solution is cooled to an internal temperature of 20 to 30 ° C., and aged at the same temperature and stirred overnight. At an internal temperature of 20 to 30 ° C., EtOAc (160 mL) was added dropwise over 1 hour, and the mixture was aged and stirred for 1 hour or more at the same temperature. The precipitated crystals were filtered. The wet crystals were washed with a solution of EtOH / EtOAc (3 mL / 12 mL). The wet crystals are dried overnight under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide Hydrobromide dihydrate crystals (Form B21, 6.05 g) were obtained.

[0044]
Example 7
(Tautomerism of each crystal)

[0045]
Example 7-1
(Crystal form conversion; hydrobromide B21 → A61)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H- Pyrrolo [2,3-b] pyridine-5-carboxamide hydrobromide dihydrate (Form B21, 300 mg) and EtOH (3 mL) were sequentially charged at room temperature and suspended overnight. After suspension, the crystals were collected by filtration at room temperature and the wet crystals were washed with EtOH. The wet crystals are dried overnight under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide Hydrobromide crystal (Form A61, 258 mg) was obtained.

[0046]
Example 7-2
(Crystal form conversion; hydrobromide B11 → B21)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H- Pyrrolo [2,3-b] pyridine-5-carboxamide hydrobromide monohydrate (form B11, 2.0 g), EtOH (7 mL), water (3 mL) were sequentially charged at room temperature and suspended overnight. It became cloudy. After suspension, the crystals were collected by filtration at room temperature and the wet crystals were washed with 70% aqueous EtOH. The wet crystals are dried overnight under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide Hydrobromide dihydrate crystals (Form B21, 1.54 g) were obtained.

[0047]
Example 7-3
(Crystal form conversion; hydrobromide A61 form → B21 form)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H- Pyrrolo [2,3-b] pyridine-5-carboxamide hydrobromide (form A61, 1.0 g), EtOH (3.5 mL) and water (1.5 mL) were sequentially charged at room temperature and suspended overnight. After suspension, the crystals were filtered at room temperature and the wet crystals were washed with 70% aqueous EtOH. The wet crystals are dried overnight under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide Hydrobromide dihydrate crystals (Form B21, 827 mg) were obtained.

[0048]
Reference Example 1
( Example of Preparation of Monohydrate Crystalline Compound (I) Free Form)
4-Chloro-1H-pyrrolo [2,3-b] pyridine-5-carboxamide (44.5 g) under nitrogen atmosphere 1s, 3R, 4s, 5S) -4-aminoadamantan-1-ol (57.0 g) and tributylamine (162.6 mL) were charged in NMP (222.5 mL), and heated and stirred at a bath temperature of 200 ° C. for 2.5 hours. The reaction solution was allowed to cool, and then the reaction solution was added dropwise while stirring in water / Et 2 O (6 L / 0.5 L), followed by stirring for 30 minutes. The obtained solid was collected by filtration, washed twice with water (400 mL), washed twice with Et 2 O (300 mL), and dried. The resulting solid was warmed to dissolve in MeOH (1.8 L) and filtered hot. The resulting mother liquor was concentrated under reduced pressure and MeOH (1.8 L) was added to the residue and heated to dissolve. The resulting solution was allowed to cool and stir, and then stirred at room temperature and aged overnight. The precipitated solid was collected by filtration, washed with EtOH and dried under reduced pressure. The resulting solid was suspended in EtOH (250 mL) and stirred at room temperature for 1 h. The solid was collected by filtration, washed with EtOH and dried under reduced pressure. The obtained solid was suspended in water (900 mL) and stirred at a bath temperature of 70 ° C. for 2 hours. The solid was collected by filtration, washed with water and dried under reduced pressure. Furthermore, the solid was suspended in water (900 mL) and stirred at a bath temperature of 70 ° C. for 2 hours. The solid is collected by filtration, washed with water and then dried under reduced pressure to give 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2 , 3-b] Pyridine-5-carboxamide monohydrate crystal (Form A01, 44 g) was obtained.

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/////////////////Peficitinib hydrobromide, Smyraf, JAPAN 2019, ペフィシチニブ臭化水素酸塩  , ASP015K, Rheumatoid Arthritis

O=C(C1=CN=C(NC=C2)C2=C1N[C@@H]3[C@]4([H])C[C@@]5([H])C[C@](C4)(O)C[C@]3([H])C5)N.[H]Br

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DR ANTHONY CRASTO

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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 PHARMACEUTICALS 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 year tenure till date Dec 2017, 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, 50 Lakh plus views on dozen plus blogs, 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 19 lakh plus views on New Drug Approvals Blog in 216 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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