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Diquafosol

July 30, 2020 3:28 am / Leave a comment

ChemSpider 2D Image | Diquafosol | C18H26N4O23P4

Diquafosol

Molecular FormulaC₁₈H₂₆N₄O₂₃P₄
Average mass790.307 Da

{Oxybis[(hydroxyphosphoryl)oxy]}bis[hydrogéno(phosphonate)] de bis{[(2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-3,4-dihydroxytétrahydro-2-furanyl]méthyle}

59985-21-6 [RN]

7828VC80FJ

8326

Bis{[(2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-3,4-dihydroxytetrahydro-2-furanyl]methyl} {oxybis[(hydroxyphosphoryl)oxy]}bis[hydrogen (phosphonate)]

Diquafosol tetrasodium

Molecular FormulaC₁₈H₂₂N₄Na₄O₂₃P₄
Average mass878.234 Da

1) uridine, 5′-(pentahydrogen tetraphosphate), P”’->5′-ester with uridine, tetrasodium salt

211427-08-6[RN]

Diquafosol tetrasodium[USAN]

uridine(5′)tetraphospho(5′)uridine tetrasodium salt

Diquafosol tetrasodium (USAN)

INS365

P1,P4-Diuridine 5′-tetraphosphate tetrasodium salt

Prolacria

U2P4

UNII:X8T9SBH9LL

INS-365; DE-089; KPY-998

Title: Diquafosol

CAS Registry Number: 59985-21-6

CAS Name: Uridine 5¢-(pentahydrogen tetraphosphate) P¢¢¢®5¢-ester with uridine

Additional Names:P1,P4-diuridine 5¢-tetraphosphate; UP4U

Molecular Formula: C18H26N4O23P4

Molecular Weight: 790.31

Percent Composition: C 27.36%, H 3.32%, N 7.09%, O 46.56%, P 15.68%

Literature References: Uridine nucleotide analog. P2Y2 purinoceptor agonist; stimulates mucin secretion from goblet cells. Prepn: M. J. Stutts, III et al.,WO9640059 (1996 to Univ. North Carolina at Chapel Hill); and receptor activity: W. Pendergast et al.,Bioorg. Med. Chem. Lett.11, 157 (2001). Ocular pharmacology: T. Fujihara et al.,J. Ocul. Pharmacol. Ther.18, 363 (2002). Review of development and therapeutic potential: J. Fischbarg, Curr. Opin. Invest. Drugs4, 1377-1383 (2003); K. K. Nichols et al.,Expert Opin. Invest. Drugs13, 47-54 (2004). Clinical trial in dry eye disease: J. Tauber et al., Cornea23, 784 (2004).

Derivative Type: Tetrasodium salt

CAS Registry Number: 211427-08-6

Manufacturers’ Codes: INS-365

Molecular Formula: C18H22N4Na4O23P4

Molecular Weight: 878.23

Percent Composition: C 24.62%, H 2.52%, N 6.38%, Na 10.47%, O 41.90%, P 14.11%

Therap-Cat: In treatment of dry eye disease.

Keywords: Purinoceptor P2Y Agonist.

Company：: Santen (Originator)
Sales：: $80 Million (Y2015);
$71.7 Million (Y2014);
$79.3 Million (Y2013);
$67.1 Million (Y2012);
$36 Million (Y2011);
ATC Code：: S01

Approved Countries or Area 2010-04-16, JAPAN

Diquafosol tetrasodium was approved by Pharmaceuticals Medical Devices Agency of Japan (PMDA) on April 16, 2010. It was developed and marketed as Diquas^® by Santen Pharmaceutical Corporation in Japan.

Diquafosol tetrasodium is a P2Y2 purinoceptor receptor agonist. It is indicated for improve dry eye symptoms by promoting secretion of mucin and water, thereby bringing the tear film closer to a normal state. No serious ocular or systemic adverse drug reactions were found during the clinical trials. Dry eye begins with symptoms of ocular discomfort such as burning, stinging or a foreign body sensation.

Diquas^® is available as solution for ophthalmic use, containing 3% of Diquafosol tetrasodium. The recommended dose is 1 drop at a time, 6 times a day.

Index：

Diquafosol (tradename Diquas) is a pharmaceutical drug for the treatment of dry eye disease. It was approved for use in Japan in 2010.^[1] It is formulated as a 3% ophthalmic solution of the tetrasodium salt.

Its mechanism of action involves agonism of the P2Y2 purinogenic receptor.^[2]

SYN

INS-365 can also been obtained by the following ways: 4) Dimerization of uridine-5′-monophosphate tributyl-ammonium salt (I) with bis(tributylammonium) pyrophosphate (II) by means of CDI, followed by purification by semipreparative ion璭xchange chromatography. 5) Dimerization of uridine-5′-monophosphate tributyl-ammonium salt (I) with pyrophosphoryl chloride (III) in pyridine, followed by chromatographic purification as before. 6) Condensation of uridine (IV) with POCl3 and bis(tributylammonium) pyrophosphate (II) by means of tributylamine in trimethyl phosphate, followed by chromatographic purification as before. 7) Dimerization of uridine-5′-diphosphate tributylammonium salt (V) by means of CDI in DMF, followed by purification over Dowex 50Wx4 Na+. 8) Condensation of uridine-5′-triphosphate tributylammonium salt (VI) with uridine-5′-monophosphate tributyl-ammonium salt (I) by means of DCC in DMF, followed by chromatographic purification as before. 9) Reaction of uridine-5′-monophosphate tributylammonium salt (I) with CDI in DMF, followed by condensation with uridine-5′-triphosphate (VI) and chromatographic purification as before.

CLIP

China

Route 1

Reference：1. WO9905155A2.

Route 2

Reference：1. WO1999005155.

2. Bioorg. Med. Chem. Lett. 2001, 11, 157-160.

Route 3

Reference：1. WO1999005155.

Route 4

Reference：1. WO2014103704.

SYN

Practical and Efficient Approach to the Preparation of Diquafosol Tetrasodium

- Pengfei Xu

Cite this: Org. Process Res. Dev. 2020, XXXX, XXX, XXX-XXX

Publication Date:June 30, 2020

https://doi.org/10.1021/acs.oprd.0c00209

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.0c00209/suppl_file/op0c00209_si_001.pdf

https://pubs.acs.org/doi/10.1021/acs.oprd.0c00209

A scalable and practical route to synthesize the P2Y2 receptor agonist diquafosol tetrasodium has been described. Diquafosol tetrasodium was obtained via a four-step process starting from commercially available 5′-uridylic acid disodium salt. The whole procedure gives the target product in a 45% overall yield with high purity (>99%). Key steps in this process including isolation of impurities and the target product by using anion-exchange resin are discussed in detail. The optimized process has been successfully demonstrated on a large scale to support the development of diquafosol tetrasodium in China.

References

^ “Santen and Inspire Announce Approval of DIQUAS for Dry Eye Treatment in Japan”. April 16, 2010.
^ Pendergast, W; Yerxa, BR; Douglass Jg, 3rd; Shaver, SR; Dougherty, RW; Redick, CC; Sims, IF; Rideout, JL (2001). “Synthesis and P2Y receptor activity of a series of uridine dinucleoside 5′-polyphosphates”. Bioorganic & Medicinal Chemistry Letters. 11 (2): 157–60. doi:10.1016/S0960-894X(00)00612-0. PMID 11206448.

Diquafosol
Names

IUPAC name [[[[(2R,3S,4R,5R)-5-(2,4-Dioxopyrimidin-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy-hydroxy-phosphoryl]oxy-hydroxy-phosphoryl]oxy-hydroxy-phosphoryl] [(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl hydrogen phosphate
Other names P1,P4-Bis(5′-uridyl) tetraphosphate; INS-365; Diquafosol tetrasodium
Identifiers
CAS Number	59985-21-6 211427-08-6 (tetrasodium salt)
3D model (JSmol)	Interactive image
ChEMBL	ChEMBL1767408 ChEMBL221326
ChemSpider	130647 130646 (tetrasodium salt)
IUPHAR/BPS	1736
PubChem CID	148197 148196 (tetrasodium salt)
UNII	7828VC80FJ
CompTox Dashboard (EPA)	DTXSID40208689
InChI [show]
SMILES [show]
Properties
Chemical formula	C₁₈H₂₆N₄O₂₃P₄
Molar mass	790.306 g·mol⁻¹
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

///////////// INS 365, Diquafosol, INS-365, DE 089, KPY 998, JAPAN 16

59985-21-6 (Diquafosol );
211427-08-6 (Diquafosol Tetrasodium);

BAY 1895344

July 27, 2020 9:00 am / 1 Comment on BAY 1895344

BAY-1895344 Structure

BAY 1895344

1876467-74-1 (free base)

(R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-3-yl)-1,7-naphthyridin-2-yl)morpholine, monohydrochloride

BAY-1895344 hydrochloride Chemical Structure

BAY-1895344

Molecular Weight	411.89
Formula	C₂₀H₂₂ClN₇O

BAY-1895344 (hydrochloride)

1876467-74-1

1876467-74-1(free base)

s8666, CCG-268786, CS-7574, HY-101566A

BAY-1895344 hydrochloride is a potent, orally available and selective ATR inhibitor, with IC₅₀ of 7 nM. Anti-tumor activity.

NMR https://file.selleckchem.com/downloads/nmr/S866603-BAY-1895344-hnmr-selleck.pdf

Biological Activity

In vitro, BAY 1895344 was shown to be a very potent and highly selective ATR inhibitor (IC50 = 7 nM), which potently inhibits proliferation of a broad spectrum of human tumor cell lines (median IC50 = 78 nM). In cellular mechanistic assays BAY 1895344 potently inhibited hydroxyurea-induced H2AX phosphorylation (IC50 = 36 nM). Moreover, BAY 1895344 revealed significantly improved aqueous solubility, bioavailability across species and no activity in the hERG patch-clamp assay. BAY 1895344 also demonstrated very promising efficacy in monotherapy in DNA damage deficient tumor models as well as combination treatment with DNA damage inducing therapies.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m²)	0.007	0.025	0.15	0.05	0.02	0.5
K_m factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B K_m
	Animal A K_m

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

Molecular Weight	375.43
Formula	C₂₀H₂₁N₇O
CAS Number	1876467-74-1
Purity	98.69%

Solubility	10 mM in DMSO
Storage	at -20°C

PAPER

Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models

Journal of Medicinal Chemistry 2020, 63, 13, 7293-7325 (Article)

Publication Date (Web):June 5, 2020DOI: 10.1021/acs.jmedchem.0c00369

https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.0c00369

2-[(3R)-3-Methylmorpholin-4-yl]-4-(1-methyl-1Hpyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine (BAY 1895344). Sulfonate 67 (500 mg, 0.95 mmol), 1- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (68) (415 mg, 1.90 mmol), 2 M aq K2CO3 solution (1.4 mL), and Pd(PPh3)2Cl2 (67 mg, 0.094 mmol) were solubilized in DME (60 mL). The reaction mixture was stirred for 20 min at 130 °C under microwave irradiation. After cooling to rt, the mixture was filtered through a silicon filter and concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica gel, hexane/EtOAc gradient 0–100%, followed by EtOAc/EtOH 9:1). The desired fractions were concentrated under reduced pressure and solubilized in concd H2SO4 (5 mL). The mixture was stirred for 3 h at rt. The mixture was then poured into ice and basified using solid NaHCO3. The suspension was filtered and the solid was stirred with EtOH at 40 °C, filtered, and dried under reduced pressure to give BAY 1895344 (280 mg, 0.75 mmol, 78%). LC-MS [Method 2]: Rt = 0.99 min. MS (ESI+): m/z = 376.1 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ = 13.44 (br s, 1H, pyrazole-NH), 8.35 (d, J = 5.32 Hz, 1H, naphthyridine), 7.56–7.68 (m, 3H, pyrazole, naphthyridine), 7.42 (br s, 1H, pyrazole), 7.27 (d, J = 5.58 Hz, 1H, naphthyridine), 6.59 (d, J = 2.03 Hz, 1H, pyrazole), 4.60–4.69 (m, 1H, morpholine), 4.23 (br d, J = 11.66 Hz, 1H, morpholine), 4.00–4.09 (m, 1H, morpholine), 3.78–3.85 (m, 1H, morpholine), 3.75 (m, 4H, methyl, morpholine), 3.69–3.74 (m, 1H, morpholine), 3.57 (m, 1H, morpholine), 1.30 (d, J = 6.59 Hz, 3H, methyl). 13C NMR (125 MHz, DMSO-d6): δ = 156.5, 145.2, 140.0, 139.6, 139.5, 138.2, 137.4, 137.4, 125.7, 117.1, 115.5, 108.2, 107.7, 70.3, 66.1, 47.3, 39.7, 37.2, 13.3. ESI-HRMS: m/z [M+H]+ calcd for C20H22N7O: 376.1886, found: 376.1879. [α]D –80.8 ± 1.04 (1.0000 g/ 100 mL CHCl3).

References

Identification of potent, highly selective and orally available ATR inhibitor BAY 1895344 with favorable PK properties and promising efficacy in monotherapy and combination in preclinical tumor models
Ulrich T, et al. AACR. 2017 July;77(13 Suppl):Abstract nr 983.

ATR inhibitor BAY 1895344 shows potent anti-tumor efficacy in monotherapy and strong combination potential with the targeted alpha therapy Radium-223 dichloride in preclinical tumor models
Antje Margret Wengner, et al. AACR 2017 July;77(13 Suppl):Abstract nr 836.

////////////s8666, CCG-268786, CS-7574, HY-101566A, BAY-1895344, BAY 1895344

CC1COCCN1C2=NC3=C(C=CN=C3C4=CC=NN4)C(=C2)C5=CC=NN5C

MK 5204

July 26, 2020 11:02 am / Leave a comment

MK 5204

(1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-21-[(2R)-2-Amino-2,3,3-trimethylbutoxy]-20-(5-carbamoyl-1,2,4-triazol-1-yl)-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid.png

CAS No:	1207751-75-4
Product Code:	BM178545

(1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-21-[(2R)-2-amino-2,3,3-trimethylbutoxy]-20-(5-carbamoyl-1,2,4-triazol-1-yl)-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid

MF: C₄₀H₆₅N₅O₅

MW: 696g/mol

MW 695.97

C40 H65 N5 O5

PAPER

https://www.sciencedirect.com/science/article/abs/pii/S0960894X20304686

Abstract

Our previously reported efforts to produce an orally active β-1,3-glucan synthesis inhibitor through the semi-synthetic modification of enfumafungin focused on replacing the C2 acetoxy moiety with an aminotetrazole and the C3 glycoside with a N,N-dimethylaminoether moiety. This work details further optimization of the C2 heterocyclic substituent, which identified 3-carboxamide-1,2,4-triazole as a replacement for the aminotetrazole with comparable antifungal activity. Alkylation of either the carboxamidetriazole at C2 or the aminoether at C3 failed to significantly improve oral efficacy. However, replacement of the isopropyl alpha amino substituent with a t-butyl, improved oral exposure while maintaining antifungal activity. These two structural modifications produced MK-5204, which demonstrated broad spectrum activity against Candida species and robust oral efficacy in a murine model of disseminated Candidiasis without the N-dealkylation liability observed for the previous lead.

MK-5204: An orally active β-1,3-glucan synthesis inhibitor ...

patent

https://patentscope.wipo.int/search/en/detail.jsf?docId=US43243783&tab=PCTDESCRIPTION&_cid=P22-KD34BU-17225-1

Patent ID	Title	Submitted Date	Granted Date
US8188085	Antifungal agents	2010-05-06	2012-05-29

ungal infection is a major healthcare problem, and the incidence of hospital-acquired fungal diseases continues to rise. Severe systemic fungal infection in hospitals (such as candidiasis, aspergillosis, histoplasmosis, blastomycosis and coccidioidomycosis) is commonly seen in neutropaenic patients following chemotherapy and in other oncology patients with immune suppression, in patients who are immune-compromised due to Acquired Immune Deficiency Syndrome (AIDS) caused by HIV infection, and in patients in intensive care. Systemic fungal infections cause ˜25% of infection-related deaths in leukaemics. Infections due to Candida species are the fourth most important cause of nosocomial bloodstream infection. Serious fungal infections may cause 5-10% of deaths in patients undergoing lung, pancreas or liver transplantation. Treatment failures are still very common with all systemic mycoses. Secondary resistance also arises. Thus, there remains an increasing need for effective new therapy against mycotic infections.

Enfumafungin is a hemiacetal triterpene glycoside that is produced in fermentations of a Hormonema spp. associated with living leaves of Juniperus communis (U.S. Pat. No. 5,756,472; Pelaez et al., Systematic and Applied Microbiology, 23:333-343, 2000; Schwartz et al., JACS, 122:4882-4886, 2000; Schwartz, R. E., Expert Opinion on Therapeutic Patents, 11(11):1761-1772, 2001). Enfumafungin is one of the several triterpene glycosides that have in vitro antifungal activities. The mode of the antifungal action of enfumafungin and other antifungal triterpenoid glycosides was determined to be the inhibition of fungal cell wall glucan synthesis by their specific action on (1,3)-β-D-glucan synthase (Onishi et al., Antimicrobial Agents and Chemotherapy, 44:368-377, 2000; Pelaez et al., Systematic and Applied Microbiology, 23:333-343, 2000). 1,3-β-D-Glucan synthase remains an attractive target for antifungal drug action because it is present in many pathogenic fungi which affords broad antifungal spectrum and there is no mammalian counterpart and as such, compounds inhibiting 1,3-β-D-Glucan synthase have little or no mechanism-based toxicity.

SIMILAR BUT NOT SAME

METHOXY EXAMPLE

Example 8

(1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3-dimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[3-(methoxycarbonyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (EXAMPLE 8A) and (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3-dimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(methoxycarbonyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (EXAMPLE 8B)

	DR ANTHONY MELVIN CR… on Pegylated Interferon alpha-2b,…
	DR ANTHONY MELVIN CR… on Sacituzumab govitecan-hziy
	DR ANTHONY MELVIN CR… on Diclofenac etalhyaluronate sod…
	DR ANTHONY MELVIN CR… on Dasiglucagon
	DR ANTHONY MELVIN CR… on Brivudine

No.	Major Technical Classification	Publication No.	Patent No.	Legal Status	Filling Date	Estimated Expiry Date
1	Uses	CN1211186A		Withdrawn	1997/2/14
2	Uses	CN1233181A	CN1229114C	Granted	1997/3/27	2017/3/27
3	Uses	CN1227491A		Withdrawn	1997/7/3
4	Uses	CN1226169A		Withdrawn	1997/7/23
5	Uses	CN1236318A	CN1115152C	Granted	1997/10/21	2017/10/21
6	Formulation	CN1250369A	CN1151775C	Granted	1998/2/6	2018/2/6
7	Salt	CN1265114A	CN1147502C	Granted	1998/7/24	2018/7/24
8	Uses	CN1348378A		Withdrawn	1999/11/19
9	Uses	CN1413113A		Withdrawn	2000/12/22
10	Uses	CN1431914A	CN100391538C	Granted	2001/5/30	2021/5/30
11	Uses	CN1501940A	CN100465186C	Granted/abandoned	2001/8/20	2011/8/20
12	Formulation	CN1406586A	CN1228053C	Granted	2002/9/10	2022/9/10
13	Uses	CN1612739A		Withdrawn	2002/11/6
14	Formulation	CN103096929A		Examination	2011/9/9
15	Formulation	CN103282039A		Examination	2011/12/27
16	Formulation	CN104203254A		Examination	2013/3/25

Patent ID	Title	Submitted Date
US2019192504	Therapeutic heterocyclic compounds	2018-08-20
US2017281627	TOLL LIKE RECEPTOR MODULATOR COMPOUNDS	2017-04-25
US2017071944	MODULATORS OF TOLL-LIKE RECEPTORS FOR THE TREATMENT OF HIV	2016-09-13
US9670205	TOLL LIKE RECEPTOR MODULATOR COMPOUNDS	2016-03-02

Clinical data

Other names	ZYAN1
Identifiers
IUPAC name [show]
CAS Number	1616690-16-4
UNII	Y962PQA4KS
Chemical and physical data
Formula	C₁₆H₁₆N₂O₆
Molar mass	332.312 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] C1CC1CON2C3=CC=CC=C3C(=C(C2=O)C(=O)NCC(=O)O)O
InChI [hide] InChI=1S/C16H16N2O6/c19-12(20)7-17-15(22)13-14(21)10-3-1-2-4-11(10)18(16(13)23)24-8-9-5-6-9/h1-4,9,21H,5-8H2,(H,17,22)(H,19,20) Key:IKRKQQLJYBAPQT-UHFFFAOYSA-N

CTID	Title	Phase	Status	Date
NCT04215120	Desidustat in the Treatment of Anemia in CKD on Dialysis Patients	Phase 3	Recruiting	2020-01-02
NCT04012957	Desidustat in the Treatment of Anemia in CKD	Phase 3	Recruiting	2019-12-24

Monthly Archives: July 2020

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Diquafosol tetrasodium

Index：

Practical and Efficient Approach to the Preparation of Diquafosol Tetrasodium

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Biological Activity

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Chemical Information

References

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Abstract

Example 8A

Example 8B

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1-Hexanol, 2-((2-amino-7-fluoropyrido(3,2-d)pyrimidin-4-yl)amino)-2-methyl-, (2R)-

(2R)-2-((2-Amino-7-fluoropyrido(3,2-d)pyrimidin-4-yl)amino)-2-methylhexan-1-ol

EXAMPLE 63

EXAMPLE 64

EXAMPLE 65

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Step 1′a Process for Preparation of ethyl 2-iodobenzoate (XI-a)

Step-2 Process for the Preparation of ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)aminolbenzoate (XII-a)

Step 3 Process for the Preparation of ethyl 2-((cyclopropylmethoxy)amino)benzoate (XIII-a)

Step 4 Process for the Preparation of ethyl 24N-(cyclopropylinethoxy)-3-ethoxy-3-oxopropanamido)benzoate (XIV-a)

Step 5: Process for the Preparation of ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2 dihydroquinolline-3-carboxylate (XY-a)

Purification

Step 6 Process for the Preparation of ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate (XVI-a)

Purification

Step 7: Process for the Preparation of (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycine (I-a)

Polymorphic Data (XRPD):

References

ANALYSIS

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