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Showing posts with label SWEDEN. Show all posts
Showing posts with label SWEDEN. Show all posts

Monday 18 May 2015

ETHYL PYRUVATE

Pyruvate structural formula
Pyruvate magnetic resonance diagram (<sup> 1 </ sup> HNMR)














ir
乙基丙酮酸酯



mass
乙基丙酮酸酯




P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.





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COCK SAYS MOM CAN TEACH YOU NMR


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Friday 8 May 2015

ELIGLUSTAT

Eliglustat.svg
ELIGLUSTAT TARTRATE
THERAPEUTIC CLAIM Treatment of lysosomal storage disorders
CHEMICAL NAMES
1. Octanamide, N-[(1R,2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-1-(1-
pyrrolidinylmethyl)ethyl]-, (2R,3R)-2,3-dihydroxybutanedioate (2:1)
2. bis{N-[(1R,2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-1-(pyrrolidin-1-
ylmethyl)ethyl]octanamide} (2R,3R)-2,3-dihydroxybutanedioate
MOLECULAR FORMULA C23H36N2O4 . ½ C4H6O6
MOLECULAR WEIGHT 479.6
MANUFACTURER Genzyme Corp.
CODE DESIGNATION Genz-112638
CAS REGISTRY NUMBER 928659-70-5
Eliglustat (INNUSAN;[1] trade name Cerdelga) is a treatment for Gaucher’s diseasedeveloped by Genzyme Corp that was approved by the FDA August 2014.[2] Commonly used as the tartrate salt, the compound is believed to work by inhibition ofglucosylceramide synthase.[3][4]
In March 2015, eliglustat tartrate was approved in Japan for the treatment of Gaucher disease. Eliglustat tartrate was described specifically within the US FDA’s Orange Booked listed US6916802, which is set to expire in April 2022.
In May 2015, the Orange Book also listed that eliglustat tartrate had Orphan Drug Exclusivity and New Chemical Entity exclusivity until 2019 and 2021, respectively.
it having been developed and launched as eliglustat tartrate by Genzyme (a wholly owned subsidiary of Sanofi), under license from the University of Michigan.
Eliglustat tartrate is known to act as inhibitors of glucosylceramide synthase and glycolipid, useful for the treatment of Gaucher’s disease type I and lysosome storage disease.

Genzyme Announces Positive New Data from Two Phase 3 Studies for Oral Eliglustat Tartrate for Gaucher Disease


Eliglustat tartrate (USAN)
CAS:928659-70-5
February 15, 2013
Genzyme , a Sanofi company (EURONEXT: SAN and NYSE: SNY), today announced positive new data from the Phase 3 ENGAGE and ENCORE studies of eliglustat tartrate, its investigational oral therapy for Gaucher disease type 1. The results from the ENGAGE study were presented today at the 9th Annual Lysosomal Disease Network WORLD Symposium in Orlando, Fla. In conjunction with this meeting, Genzyme also released topline data from its second Phase 3 study, ENCORE. Both studies met their primary efficacy endpoints and together will form the basis of Genzyme’s registration package for eliglustat tartrateThe data presented at this year’s WORLD symposium reinforce our confidence that eliglustat tartrate may become an important oral option for patients with Gaucher disease”The company is developing eliglustat tartrate, a capsule taken orally, to provide a convenient treatment alternative for patients with Gaucher disease type 1 and to provide a broader range of treatment options for patients and physicians. Genzyme’s clinical development program for eliglustat tartrate represents the largest clinical program ever focused on Gaucher disease type 1 with approximately 400 patients treated in 30 countries.“The data presented at this year’s WORLD symposium reinforce our confidence that eliglustat tartrate may become an important oral option for patients with Gaucher disease,” said Genzyme’s Head of Rare Diseases, Rogerio Vivaldi MD. “We are excited about this therapy’s potential and are making excellent progress in our robust development plan for bringing eliglustat tartrate to the market.”ENGAGE Study Results:In ENGAGE, a Phase 3 trial to evaluate the safety and efficacy of eliglustat tartrate in 40 treatment-naïve patients with Gaucher disease type 1, improvements were observed across all primary and secondary efficacy endpoints over the 9-month study period. Results were reported today at the WORLD Symposium by Pramod Mistry, MD, PhD, FRCP, Professor of Pediatrics & Internal Medicine at Yale University School of Medicine, and an investigator in the trial.The randomized, double-blind, placebo-controlled study had a primary efficacy endpoint of improvement in spleen size in patients treated with eliglustat tartrate. Patients were stratified at baseline by spleen volume. In the study, a statistically significant improvement in spleen size was observed at nine months in patients treated with eliglustat tartrate compared with placebo. Spleen volume in patients treated with eliglustat tartrate decreased from baseline by a mean of 28 percent compared with a mean increase of two percent in placebo patients, for an absolute difference of 30 percent (p<0.0001).

Genzyme

Eliglustat tartate (Genz-112638)

What is Eliglustat?
  • Eliglustat is a new investigational phase 3 compound from Genzyme Corporation that is being studied for type 1 Gaucher Disease.
  • Eliglustat works as a substrate reduction therapy by reducing glucocerebroside. formation.
  • This product is an oral agent (i.e. a pill) that is taken once or twice a day in contrast to an IV infusion for enzyme replacement therapy. Enzyme replacement therapy focuses on replenishing the enzyme that is deficient in Gaucher Disease and breaks down glucocerebroside that accumulates.
  • The clinical trials for eliglustat tartate are sponsored by Genzyme Corporation.
Eliglustat tartrate (Genz-1 12638) is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of gaucher disease and other lysosomal storage disorders, which is currently under development.
Eliglustat is chemically known as 1 R, 2R-Octanoic acid [2-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1 -ylmethyl]-ethyl]-amide, having a structural formula I depicted here under.
Formula I
Eliglustat hemitartrate (Genz-1 12638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy.
Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase.
U.S. patent No. 7,196,205 (herein described as US’205) discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof. In this patent, eliglustat was synthesized via a seven-step process involving steps in that sequence:
(i) coupling S-(+)-2-phenyl glycinol with phenyl bromoacetate followed by column chromatography for purification of the resulting intermediate,
(ii) reacting the resulting (5S)-5-phenylmorpholin-2-one with 1 , 4-benzodioxan-6-carboxaldehyde to obtain a lactone,
(iii) opening the lactone of the oxazolo-oxazinone cyclo adduct via reaction with pyrrolidine,
(iv) hydrolyzing the oxazolidine ring, (v) reducing the amide to amine to obtain sphingosine like compound, (vi) reacting the resulting amine with octanoic acid and N-hydroxysuccinimide to obtain crude eliglustat, (vii) purifying the crude eliglustat by repeated isolation for four times from a mixture of ethyl acetate and n-heptane.
U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 disclose processes for preparation of eliglustat and intermediates thereof.
U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of eliglustat, (ii) a hemitartrate salt of eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.
WO 2015059679
Process for the preparation of eliglustat free base – comprising the reaction of S-(+)-phenyl glycinol with phenyl-alpha-bromoacetate to obtain 5-phenylmorpholin-2-one, which is further converted to eliglustat.
Dr Reddy’s Laboratories Ltd
New crystalline eliglustat free base Form R1 and a process for its preparation are claimed. Also claimed is a process for the preparation of eliglustat free base which comprises the reaction of S-(+)-phenyl glycinol with phenyl-alpha-bromoacetate to obtain 5-phenylmorpholin-2-one, which is further converted to eliglustat.Further eliglustat oxalate, its crystalline form, and a process for the preparation of crystalline eliglustat oxalate, are claimed.
Eliglustat tartrate (Genz-1 12638) is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of gaucher disease and other lysosomal storage disorders, which is currently under development.
Eliglustat is chemically known as 1 R, 2R-Octanoic acid [2-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1 -ylmethyl]-ethyl]-amide, having a structural formula I depicted here under.
Formula I
Eliglustat hemitartrate (Genz-1 12638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy.
Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase.
U.S. patent No. 7,196,205 (herein described as US’205) discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof. In this patent, eliglustat was synthesized via a seven-step process involving steps in that sequence:
(i) coupling S-(+)-2-phenyl glycinol with phenyl bromoacetate followed by column chromatography for purification of the resulting intermediate,
(ii) reacting the resulting (5S)-5-phenylmorpholin-2-one with 1 , 4-benzodioxan-6-carboxaldehyde to obtain a lactone,
(iii) opening the lactone of the oxazolo-oxazinone cyclo adduct via reaction with pyrrolidine,
(iv) hydrolyzing the oxazolidine ring, (v) reducing the amide to amine to obtain sphingosine like compound, (vi) reacting the resulting amine with octanoic acid and N-hydroxysuccinimide to obtain crude eliglustat, (vii) purifying the crude eliglustat by repeated isolation for four times from a mixture of ethyl acetate and n-heptane.
U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 disclose processes for preparation of eliglustat and intermediates thereof.
U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of eliglustat, (ii) a hemitartrate salt of eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.
Example 1 : Preparation of 5-phenyl morpholine-2-one hydrochloride
To a (S) + phenyl glycinol (100g) add N, N-diisopropylethylamine (314ml) and acetonitrile (2000ml) under nitrogen atmosphere at room temperature. It was cooled to 10- 15° C. Phenyl bromoacetate (172.4g) dissolved in acetonitrile (500ml) was added to the above solution at 15° C over a period of 30 min. The reaction mixture is allowed to room temperature and stirred for 16-20h. Progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at a water bath
temperature less than 25° C to get a residue. The residue was dissolved in ethyl acetate (1000ml) and stirred for 1 h at 15-20°C to obtain a white solid. The solid material obtained was filtered and washed with ethyl acetate (200ml). The filtrate was dried over anhydrous sodium sulphate (20g) and concentrated under reduced pressure at a water bath temperature less than 25° C to give crude compound (1000g) as brown syrup. The Crude brown syrup is converted to HCI salt by using HCI in ethyl acetate to afford 5-phenyl morpholine-2-one hydrochloride (44g) as a white solid. Yield: 50%, Mass: m/z = 177.6; HPLC (% Area Method): 90.5%
Example 2: Preparation of (1 R,3S,5S,8aS)-1 ,3-Bis-(2′,3′-dihydro-benzo[1 ,4] dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one.
5-phenyl morpholine-2-one hydrochloride (100g) obtained from above stage 1 is dissolved in toluene (2500ml) under nitrogen atmosphere at 25-30°C. 1 ,4-benzodioxane-6-carboxaldehyde (185.3g) and sodium sulphate (400g) was added to the above solution and the reaction mixture was heated at 100-105°C for 72h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature less than 25° C to get a residue. The residue was cooled to 10°C, ethyl acetate (2700ml) and 50% sodium bisulphate solution (1351 ml) was added to the residue and stirred for 1 h at 10°C to obtain a white solid. The obtained white solid was filtered and washed with ethyl acetate. The separated ethyl acetate layer was washed with water (1000ml), brine (1000ml) and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure at a water bath temperature of 45-50°C to get a crude material. The obtained crude material is triturated with diethyl ether (1500ml) to get a solid material which is filtered and dried under vacuum at room temperature for 2-3h to afford (1 R,3S,5S,8aS)-1 ,3-Bis-(2′,3′-dihydro-benzo[1 ,4]dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one (148g) as a yellow solid. Yield: 54%, Mass: m/z = 487.7; HPLC (% Area Method): 95.4 %
Example 3: Preparation of (2S,3R,1 “S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)-3-hydroxy-2-(2″-hydroxy-1 ”^henyl-ethy^
(1 R,3S,5S,8aS)-1 !3-Bis-(2′!3′-dihydro-benzo[1 ,4]dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one (70g) obtained from above stage 2 was dissolved in chloroform (1400ml) at room temperature. It was cooled to 0-5°C and pyrrolidone (59.5ml) was added at 0-5°C over a period of 30 minutes. The reaction mixture was allowed to room temperature and stirred for 16-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature of 40-45°C to obtain a crude. The obtained crude was dissolved in methanol (1190ml) and 1 N HCI (1 190ml) at 10-15° C, stirred for 10 minutes and heated at 80-85°C for 7h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, methanol was concentrated under reduced pressure at a water bath temperature of 50-55°C.The aqueous layer was extracted with ethyl acetate and the organic layer was washed with 1 N HCI (50ml). The aqueous layer was basified with saturated sodium bicarbonate solution up to pH 8-9 and extracted with ethyl acetate (3x70ml). The combined organic layers was washed with brine (100ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure at a water bath temperature of 50-55°C to afford (2S,3R,1″S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)-3-hydroxy-2-(2″-hydroxy-1 “-phenyl-ethylamino)-1 -pyrrolidin-1 -yl-propan-1 -one (53g) as a yellow foamy solid. Yield: 90%, Mass: m/z = 412.7, HPLC (% Area Method): 85.1 %
Example 4: Preparation of (1 R,2R,1 “S)-1-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)2-hydroxy-2-(2″-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1-yl-propan-1-ol.
(2S,3R,1 “S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)-3-hydroxy-2-(2″-hydroxy-1 “-phenyl-ethylamino)-1 -pyrrolidin-1 -yl-propan-1 -one (2.5g) obtained from above stage 3 dissolved in Tetrahydrofuran (106ml) was added to a solution of Lithium aluminium hydride (12.2g) in tetrahydrofuran (795ml) at 0°C and the reaction mixture was heated at 60-65°C for 10h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 5- 10°C and quenched in saturated sodium sulphate solution (100ml) at 5-10°C. Ethyl acetate was added to the reaction mass and stirred for 30-45 min. The obtained solid is filtered through celite bed and washed with ethyl acetate. Filtrate was dried over anhydrous sodium sulphate and concentrated under reduced pressure at a water bath temperature of 50°C to afford (1 R,2R, 1″S)-1 -(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)2-hydroxy-2-(2″-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1 -yl-propan-1 -ol (43.51 g) as a yellow gummy liquid. The crude is used for the next step without further purification. Yield: 85%, Mass: m/z = 398.7, HPLC (% Area Method): 77 %
Example 5: Preparation of (1 R, 2R)-2-Amino-1-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol.
(1 R,2R,1 “S)-1 -(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)2-hydroxy-2-(2″-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1 -yl-propan-1 -ol (40g) obtained from above stage 4 was dissolved in methanol (400ml) at room temperature in a 2L hydrogenation flask. Trifluoroacetic acid (15.5ml) and 20% Pd (OH) 2 (40g) was added to the above solution under nitrogen atmosphere. The reaction mixture was hydrogenated under H2, 10Opsi for 16-18h at room temperature. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was filtered through celite bed and washed with methanol (44ml) and water (44ml). Methanol was concentrated under reduced pressure at a water bath temperature of 50-55°C and the aqueous layer was washed with ethyl acetate. The aqueous layer was basified with 10M NaOH till the PH reaches 12-14 and then extracted with dichloromethane (2x125ml). The organic layer was dried over anhydrous sodium sulphate (3gm) and concentrated under reduced pressure at a water bath temperature of 45°C to obtain a gummy liquid. The gummy liquid was triturated with methyl tertiary butyl ether for 1 h to get a white solid, which is filtered and dried under vacuum at room temperature to afford (1 R, 2R)-2-Amino-1 -(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol (23g) as a white solid. Yield: 82.3%, Mass (m/zj: 278.8, HPLC (% Area Method): 99.5%, Chiral HPLC (% Area Method): 97.9%
Example 6: Preparation of Eliglustat {(1 R, 2R)-Octanoic acid[2-(2′,3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1-ylmethyl-ethyl]-amide}.
(1 R, 2R)-2-Amino-1 -(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol (15g) obtained from above stage 5 was dissolved in dry dichloromethane (150ml) at room temperature under nitrogen atmosphere and cooled to 10-15° C. Octanoic acid N-hydroxy succinimide ester (13.0 g)was added to the above reaction mass at 10-15° C and stirred for 15 min. The reaction mixture was stirred at room temperature for 16h-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 15°C and diluted with 2M NaOH solution (100 ml_) and stirred for 20 min at 20 °C. The organic layer was separated and washed with 2M sodium hydroxide (3x90ml).The organic layer was dried over anhydrous sodium sulphate (30g) and concentrated under reduced pressure at a water bath temperature of 45°C to give the crude compound (20g).The crude is again dissolved in methyl tertiary butyl ether (25 ml_) and precipitated with Hexane (60ml). It is stirred for 10 min, filtered and dried under vacuum to afford Eliglustat as a white solid (16g). Yield: 74%, Mass (m/zj: 404.7 HPLC (% Area Method): 97.5 %, ELSD (% Area Method): 99.78%, Chiral HPLC (% Area Method): 99.78 %.
Example 7: Preparation of Eliglustat oxalate.
Eliglustat (5g) obtained from above stage 6 is dissolved in Ethyl acetate (5ml) at room temperature under nitrogen atmosphere. Oxalic acid (2.22g) dissolved in ethyl acetate (5ml) was added to the above solution at room temperature and stirred for 14h. White solid observed in the reaction mixture was filtered and dried under vacuum at room temperature for 1 h to afford Eliglustat oxalate as a white solid (4g). Yield: 65.46%, Mass (m/zj: 404.8 [M+H] +> HPLC (% Area Method): 95.52 %, Chiral HPLC (% Area Method): 99.86 %
……………………………..
Nmr predict
N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide NMR spectra analysis, Chemical CAS NO. 491833-29-5 NMR spectral analysis, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide H-NMR spectrum
13 C NMR
N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide NMR spectra analysis, Chemical CAS NO. 491833-29-5 NMR spectral analysis, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide C-NMR spectrum
CAS NO. 491833-29-5, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide
C-NMR spectral analysis
………………..
Figure imgf000024_0001
Compound 7
(1R,2R)-Nonanoic acid[2-(2′,3′-dihydro-benzo[1,4]dioxin-6′-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide
Figure US07196205-20070327-C00026
This compound was prepared by the method described for Compound 6 using Nonanoic acid N-hydroxysuccinimide ester. Analytical HPLC showed this material to be 98.4% pure. mp 74–75° C.
1H NMR (CDCl3) δ 6.86–6.76 (m, 3H), 5.83 (d, J=7.3 Hz, 1H), 4.90 (d, J=3.3 Hz, 1H), 4.24 (s, 4H), 4.24–4.18 (m, 1H), 2.85–2.75 (m, 2H), 2.69–2.62 (m, 4H), 2.10 (t, J=7.3 Hz, 2H), 1.55–1.45 (m, 2H), 1.70–1.85 (m, 4H), 1.30–1.15 (m, 10H), 0.87 (t, J=6.9 Hz, 3H) ppm.
Intermediate 4(1R,2R)-2-Amino-1-(2′,3′-dihydro-benzo[1,4]dioxin-6′-yl)-3-pyrrolidin-1-yl-propan-1-ol
Figure US07196205-20070327-C00023
Intermediate 3 (5.3 g, 13.3 mmol) was dissolved in methanol (60 mL). Water (6 mL) and trifluoroacetic acid (2.05 m/L, 26.6 mmol, 2 equivalents) were added. After being placed under nitrogen, 20% Palladium hydroxide on carbon (Pearlman’s catalysis, Lancaster or Aldrich, 5.3 g) was added. The mixture was placed in a Parr Pressure Reactor Apparatus with glass insert. The apparatus was placed under nitrogen and then under hydrogen pressure 110–120 psi. The mixture was stirred for 2–3 days at room temperature under hydrogen pressure 100–120 psi. The reaction was placed under nitrogen and filtered through a pad of celite. The celite pad was washed with methanol (100 mL) and water (100 mL). The methanol was removed by rotoevaporation. The aqueous layer was washed with ethyl acetate three times (100, 50, 50 mL). A 10 M NaOH solution (10 mL) was added to the aqueous layer (pH=12–14). The product was extracted from the aqueous layer three times with methylene chloride (100, 100, 50 mL). The combined organic layers were dried with Na2SO4, filtered and rotoevaporated to a colorless oil. The foamy oil was vacuum dried for 2 h. Intermediate 4 was obtained in 90% yield (3.34 g).
Intermediate 3(1R,2R,1″S)-1-(2′,3′-Dihydro-benzo[1,4]dioxin-6′-yl)-2-(2″-hydroxy -1′-phenyl-ethylamino)-3-pyrrolidin-1-yl-propan-1-ol
Figure US07196205-20070327-C00022
To a 3-neck flask equipped with a dropping funnel and condenser was added LiAlH4(Aldrich, 1.2 g, 31.7 mmol, 2.5 equivalents) and anhydrous THF (20 mL) under nitrogen. A solution of Intermediate 2 (5.23 g, 12.68 mmol) in anhydrous THF (75 mL) was added dropwise to the reaction over 15–30 minutes. The reaction was refluxed under nitrogen for 9 hours. The reaction was cooled in an ice bath and a 1M NaOH solution was carefully added dropwise. After stirring at room temperature for 15 minutes, water (50 mL) and ethyl acetate (75 mL) was added. The layers were separated and the aqueous layer was extracted twice with ethyl acetate (75 mL). The combined organic layers were washed with saturated sodium chloride solution (25 mL). After drying with Na2SOthe solution was filtered and rotoevaporated to yield a colorless to yellow foamy oil. Intermediate 3 was obtained in 99% yield (5.3 g).
………………..
SWEDEN
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Sunday 22 February 2015

NMR DATA.....LEARN FROM COCK




Cock says use the above scheme to understand from basics the 1H NMR, 13C NMR, IR ETC, the below data will help you to systematically understand the signals ...happy learning online

Starting material is shown/described below




.



13 C NMR

.

1H NMR




START THE EXERCISE OF LEARNING..............................

1-(4-Nitrophenyl)piperidin-2-one (11)[ 7 ]

A solution of 5-chloropentanoyl chloride (12.9 mL, 15.50 g, 0.10 mol) in tetrahydrofuran (THF, 20 mL) was added below 5 °C to a solution of 4-nitroaniline (11.05 g, 0.08 mol) and triethylamine (22.5 mL, 0.16 mol) in THF (50 mL). The mixture was stirred at room temperature under N2 for 5 h. Potassium tert-butoxide (24.70 g, 0.22 mol) was added to the reaction solution in batches below 5 °C during 30 min and then stirred at room temperature for 2 h. The suspension was concentrated to dryness and redissolved in ethyl acetate (100 mL) and water (100 mL) to separate the organic phase. The aqueous phase was extracted with ethyl acetate (2 × 80 mL) and washed with water (2 × 80 mL) and brine (80 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated completely to get a yellow solid. The recrystallization of the crude product from ethyl acetate afforded 11 as a pale yellow solid. Yield: 15.13 g, 86%;

 IGNORE ABOVE SYNTHETIC SCHEME AND TRY TO UNDERSTAND THE SIGNALS


mp 97–99 °C; 

IR (KBr, cm−1): 3015 and 2958 (C-H aliphatic), 1656 (C˭O stretching), 1520 (aromatic C˭C), 1477, 1343 (N˭O stretching), 1308 and 1168 (C-N stretching), 860 and 698 (Ar-H aromatic bending); 

1H NMR (500 MHz, CDCl3, ppm),  
δ: 8.25 (d, J = 8.8 Hz, 2H), aromatic H ortho to nitro
7.50 (d, J = 8.8 Hz, 2H), 
3.73 (t, J = 5.8 Hz, 2H), 
2.62 (t, J = 6.5 Hz, 2H), 
1.96–2.01 (m, 4H); 

13C NMR (125 MHz, CDCl3, ppm), δ: 170.3, 150.0, 145.2, 125.9 (2C), 124.3 (2C), 50.9, 33.1, 23.4, 21.2; 


MS/EI m/z = 220.1 (M+).

 COCK WILL TEACH YOU

3-Morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one (12)[ 7 ]

Phosphorus pentachloride (18.7 g, 0.09 mol) was slowly added to a solution of 11 (6.6 g, 0.03 mol) in chloroform (40 mL) at room temperature. The resulting mixture was heated to reflux for 3 h, poured into ice water, and extracted with chloroform (3 × 30 mL). The combined organic phase was washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. The residue was dissolved in morpholine (30 mL) and refluxed for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting solid was redissolved in water, and the precipitate was filtered. The recrystallization of the filter cake from ethyl acetate afforded 12 as a yellow solid. Yield: 7.08 g, 78%; 
mp 158–160 °C; 
IR (KBr, cm−1): 2814 (C-H aliphatic), 1673 (C˭O stretching), 1626 (aliphatic C˭C), 1591 and 1510 (aromatic C˭C), 1487 (N˭O stretching), 1350 (C-N stretching), 1112 (C-O stretching), 835 and 783 (Ar-H aromatic bending);

 1H NMR (500 MHz, CDCl3, ppm), δ: 8.25 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 8.9 Hz, 2H), 5.80 (t, J = 4.1 Hz, 1H), 3.84–4.01 (m, 6H), 2.83–2.96 (m, 4H), 2.54–2.68 (m, 2H);

 13C NMR (125 MHz, CDCl3, ppm), δ: 161.3, 148.4, 144.6, 143.5, 124.6 (2C), 124.1 (2C), 115.7, 66.7 (2C), 50.5 (2C), 48.3, 23.3; 

MS/EI m/z = 303.1 (M+).


 COCK WILL TEACH YOU



1-(4-Aminophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one (13)

A solution of sodium sulfide nonahydrate (9.60 g, 0.04 mol) in water (20 mL) was added to a solution of 12 (6.07 g, 0.02 mol) in ethanol (60 mL). The mixture was heated to 50 °C and stirred for 4 h, cooled to room temperature, and concentrated in vacuo. The residue was added to ethyl acetate (60 mL), heated to boiling, and filtered. The filtrate was concentrated in vacuo to dryness to yield 13 as a pale yellow solid. Yield: 4.92 g, 90%; 

mp 180–182 °C; 

IR (KBr, cm−1): 3428 and 3350 (N-H stretching), 2811 (C-H aliphatic), 1656 (C˭O stretching), 1610 (aliphatic C˭C), 1519 and 1444 (aromatic C˭C), 1260 (C-N stretching), 1131 and 1117 (C-O stretching), 765 and 748 (Ar-H aromatic bending);

 1H NMR (500 MHz, CDCl3, ppm), δ: 7.09 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 5.52–5.70 (m, 1H), 3.75–3.90 (m, 4H), 3.53–3.71 (m, 4H), 2.83–3.10 (m, 4H), 2.42–2.59 (m, 2H);

13C NMR (125 MHz, DMSO-d 6, ppm), δ: 160.6, 146.7, 143.1, 131.9, 126.4 (2C), 113.7, 113.5 (2C), 65.9 (2C), 49.9 (2C), 48.9, 22.9;

 MS/EI m/z = 273.2 (M+). HRMS/EI calcd. for C15H19N3O2: 273.1477; found: 273.1468.
COCK TEACHES


3-Morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one (4)[ 6 ]

A solution of 5-chloropentanoyl chloride (1.6 mL, 1.94 g, 12.5 mmol) in THF (10 mL) was added to a solution of 13 (2.73 g, 10 mmol) and triethylamine (2.8 mL, 20 mmol) in THF (75 mL) below 5 °C. The mixture was stirred at 50 °C under N2 for 2 h. Potassium tert-butoxide (3.37 g, 30 mmol) was added to the reaction solution in batches below 5 °C during 30 min and then stirred at 50 °C for 8 h. The suspension was cooled to room temperature and concentrated in vacuo to dryness. The residue was dissolved in water, stirred, and then filtered. The filter cake was washed with water and dried to afford 4 as a white solid. Yield: 3.02 g, 85%; 

mp 204–206 °C;


IR (KBr, cm−1): 2965, 2852 and 2803 (C-H aliphatic), 1646 (C˭O stretching), 1616 (aliphatic C˭C), 1514 and 1463 (aromatic C˭C), 1262 (C-N stretching), 1114, 1070 and 1050 (C-O stretching), 835 and 783 (Ar-H aromatic bending);


1H NMR (500 MHz, CDCl3, ppm), δ: 7.35 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 5.66 (t, J = 4.3 Hz, 1H), 3.78–3.86 (m, 6H), 3.60–3.65 (m, 2H), 2.82–2.90 (m, 4H), 2.43–2.59 (m, 2H), 2.24–2.41 (m, 2H), 1.93–2.01 (m, 4H);

13C NMR (125 MHz, CDCl3, ppm), δ: 170.8, 162.1, 144.3, 141.7, 141.5, 127.3(2C), 126.4(2C), 115.1, 67.4(2C), 52.3, 51.1(2C), 49.2, 33.5, 24.2, 24.0, 22.1;

MS/EI m/z = 355.2 (M+). HRMS/EI calcd. for C20H25N3O3: 355.1896; found: 355.1906.





HE TAUGHT YOU STEPWISE



(Z)-Ethyl 2-Chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (3)[ 4 , 11–13 ]

Hydrochloric acid (35–36%, 6 mL, 60 mmol) was added to a solution of 4-methoxyaniline (2.46 g, 20 mmol) in water (12 mL) at −5 to 0°C. A solution of sodium nitrite (1.66 g, 24 mmol) in water (8 mL) was added to the mixture dropwise below 0 °C. Then, the reaction solution was stirred for 30 min at 0 °C, followed by the addition of sodium acetate (3.28 g, 40 mmol) until pH 5–6. After that, a solution of ethyl 2-chloroacetoacetate (2.8 mL, 3.28 g, 20 mol) in methanol (30 mL) was added dropwise to the reaction mixture at 0 to 5 °C. The resulting solution was stirred at room temperature for 4 h. The solution was removed from the mixture in vacuo, and the residue was dissolved in water (10 mL) and ethyl acetate (20 mL). The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (2 × 10 mL). The combined organic phase was washed with water (2 × 10 mL) and brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtrated, and concentrated thoroughly. The recrystallization of the crude product from ethyl acetate afforded 3 as a pale yellow solid. Yield: 3.94 g, 77%; 

mp 106-109 °C;
IR (KBr, cm−1): 3465 and 3257 (N-H stretching), 2999 and 2933 (C-H aliphatic), 1709 (C˭O stretching), 1519 and 1498 (aromatic C˭C), 1298 and 1226 (C-N stretching), 1169 and 1083 (C-O stretching), 820 and 745 (Ar-H aromatic bending); 

1H NMR (500 MHz, CDCl3, ppm), δ: 8.27 (s, 1H), 7.17 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H);

 13C NMR (125 MHz, CDCl3, ppm), δ: 159.8, 155.9, 135.4, 115.8 (2C), 115.0, 114.8 (2C), 62.6, 55.6, 14.3;

 MS/EI m/z = 256.1(M+).


NMR IS EASY





Ethyl 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (2)[ 7 ]

Compound 4 (1.42 g, 4.0 mmol), triethylamine (1.7 mL, 12 mmol), and potassium iodide (0.064 g, 0.4 mmol) ware added to a solution of 3 (1.13 g, 4.4 mmol) in ethyl acetate (40 mL) at room temperature. The mixture was stirred for 6 h under reflux and then cooled to 0 °C. The resulting mixture was added dropwise with 4.0 N hydrochloric acid (5 mL, 20 mmol) and stirred at room temperature for 2 h. Thereafter, water (10 mL) was added to the mixture to separate the organic layer. The aqueous layer was extrated with ethyl acetate (3 × 10 mL), and then the combined organic extracts were washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. Recrystallization of the residue from ethyl acetate and drying in vacuo afforded 2 as a pale yellow solid. Yield: 1.46 g, 75%; 

mp 120–124 °C; 

IR (KBr, cm−1): 2936 and 2873 (C-H aliphatic), 1711 (C˭N stretching), 1658 (C˭O stretching), 1609 (aliphatic C˭C), 1558, 1513, 1482 and 1460 (aromatic C˭C), 1325, 1302 and 1254 (C-N stretching), 1144, 1088 and 1027 (C-O stretching), 833, 802 and 765 (Ar-H aromatic bending); 

1H NMR (500 MHz, CDCl3, ppm), δ: 7.49 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.48 (q, J = 7.0 Hz, 2H), 4.15 (t, J = 3.2 Hz, 2H), 3.82 (s, 3H), 3.61 (t, J = 5.6 Hz, 2H), 3.33 (t, J = 6.8 Hz, 2H), 2.57 (t,J = 5.6 Hz, 2H), 1.94–2.00 (m, 4H), 1.45 (t, J = 7.0 Hz, 3H); 

13C NMR (125 MHz, CDCl3, ppm), δ: 170.8, 162.8, 160.5, 157.9, 142.1, 140.6, 139.7, 133.7, 133.2, 127.63 (2C), 127.56, 127.44 (2C), 126.9 (2C), 114.3 (2C), 61.9, 56.2, 52.3, 51.6, 33.5, 24.2, 22.2, 22.1, 15.1; 

MS/EI m/z = 488.2 (M+).

NMR IS EASY





1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (1)[ 7 ]

To the advanced intermediate 2 (2.44 g, 5.0 mmol) was added 25% ammonia water (1.5 mL, 20 mmol) in methanol (20 mL), and the mixture was heated to 65 °C for 5 h in an autoclave of 50 mL. The resulting mixture was cooled to room temperature, poured into water (30 mL), and crystalized below 0°C. The precipitate was filtrated and dried in vacuo at 50°C to afford the desired product 1 as a pale white solid. Yield: 2.09 g, 91%;


APIXABAN

mp 171–173 °C; 

IR (KBr, cm−1): 3448 and 3298 (N-H stretching), 2940 (C-H aliphatic), 1669 (C˭N stretching), 1614 (C˭O stretching), 1544 (aliphatic C˭C), 1513, 1463 and 1441 (aromatic C˭C), 1334, 1300 and 1254 (C-N stretching), 1146, 1111, 1090 and 1024 (C-O stretching), 835, 816, 794 and 758 (Ar-H aromatic bending); 

1H NMR (500 MHz, CDCl3, ppm), δ: 7.48 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 5.66 (brs, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.84 (s, 3H), 3.55–3.65 (m, 2H), 3.39 (t, J = 5.6 Hz, 2H), 2.57 (t, J = 6.2 Hz, 2H), 1.91–2.01 (m, 4H); 

13C NMR (125 MHz, CDCl3, ppm), δ: 170.9, 164.4, 160.5, 158.0, 142.1, 140.6 (2C), 134.0, 133.2, 127.4 (4C), 126.9 (2C), 126.5, 114.4 (2C), 56.2, 52.3, 51.8, 33.5, 24.2, 22.1, 21.9; 
MS/EI m/z = 459.2 (M+).



 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxamide NMR spectra analysis, Chemical CAS NO. 503612-47-3 NMR spectral analysis, 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxamide H-NMR spectrum



1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxamide NMR spectra analysis, Chemical CAS NO. 503612-47-3 NMR spectral analysis, 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxamide C-NMR spectrum





SO EASY

This is picked up from

Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry

Volume 43, Issue 1, 2013

DOI:10.1080/00397911.2011.591956, http://www.tandfonline.com/doi/full/10.1080/00397911.2011.591956#CIT0006
Jian'an Jianga & Yafei Jia*
pages 72-79


REFERENCES

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  • 2. Schumacher , W. A. ; Bostwick , J. S. ; Stewart , A. B. ; Steinbacher , T. E. ; Xin , B. M. ; Wong , P. C. Effect of the direct factor Xa inhibitor apixaban in rat models of thrombosis and hemostasis . J. Cardiovasc. Pharm. 2010 , 55 , 609 – 616 .[CrossRef][PubMed][Web of Science ®]
  • 3. Buller , H. ; Deitchman , D. ; Prins , M. ; Segers , A. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis: The Botticelli DVT dose-ranging study . J. Thromb. Haemost. 2008 , 6 , 1313 – 1318 .[CrossRef][PubMed][Web of Science ®]
  • 4. Becker , R. C. ; Alexander , J. H. ; Newby , L. K. ; Yang , H. Q. ; Barrett , Y. C. ; Mohan , P. ; Wang , J. ; Harrington , R. A. ; Wallentin , L. C. Effect of apixaban, an oral and direct factor Xa inhibitor, on coagulation activity biomarkers following acute coronary syndrome . Thromb. Haemost. 2010 , 104 , 976 – 983 . [CrossRef][PubMed][Web of Science ®]
  • 5. Turpie , A. G. G. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases . Arterioscler. Thromb. Vasc. Biol. 2007 , 27 , 1238 – 1247 . [CrossRef][PubMed][Web of Science ®]
  • 6. Zhou , J. C. ; Oh , L. M. ; Ma , P. ; Li , H. Y. Synthesis of 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones. WO Patent 2003/0 49681, June 19 , 2003 .
  • 7. Pinto , D. J. P. ; Orwat , M. J. ; Koch , S. ; Rossi , K. A. ; Alexander , R. S. ; Smallwood , A. ; Wong , P. C. ; Rendina , A. R. ; Luettgen , J. M. ; Knabb , R. M. ; He , K. ; Xin , B. M. ; Wexler , R. R. ; Lam , P. Y. S. Discovery of 1-(4-methoxypheny)-7-oxo-6-(-4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa .J. Med. Chem. 2007 , 50 , 5339 – 5356 . [CrossRef][PubMed][Web of Science ®]
  • 8. Gant , T. G. ; Shahbaz , M. Pyrazole carboxamide inhibitors of factor Xa. WO Patent 2010/030983, March 18 , 2010 .
  • 9. Yadav , G. D. ; Lande , S. V. Liquid–liquid–liquid phase-transfer catalysis: A novel and green concept for selective reduction of substituted nitroaromatics . Adv. Synth. Catal. 2005 , 347 , 1235 – 1241 . [CrossRef][Web of Science ®]
  • 10. Salan , Ü. ; Altındal , A. ; Bulut , M. ; Bekaroğlu , Ö. Synthesis and characterization of a new trans-2,2-azoquinoxaline bridged bisphthalocyanine . Tetrahedron Lett. 2005 , 46 , 6057 – 6061 . [CrossRef][Web of Science ®]
  • 11. Matiichuk , V. S. ; Potopnyk , M. A. ; Obushak , N. D. Molecular design of pyrazolo[3,4-d]pyridazines . Russ. J. Org. Chem.2008 , 44 , 1352 – 1361 . [CrossRef][Web of Science ®]
  • 12. Bianca , F. B. ; Mauro , C. F. ; Denis , G. ; Locatelli , E. ; Ricci , A. 1,3-Dipolar cycloaddition of nitrile imines with functionalized acetylenes: Regiocontrolled Sc(OTf)3-catalyzed synthesis of 4- and 5-substituted pyrazoles . Synlett 2009 , 14 , 2328 – 2332
  • 13. Anderson , W. K. ; Jones , A. N. Synthesis and evaluation of furan, thiophene, and azole bis[(carbamoyloxy)methyl] derivatives as potential antineoplastic agents . J. Med. Chem. 1984 , 27 , 1559 – 1565 . [CrossRef][PubMed][Web of Science ®]

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KHAJURAHO INDIA

Khajuraho Group of Monuments is located in India
Khajuraho Group of Monuments
Location of Khajuraho Group of Monuments in India.

Location in Madhya PradeshLocation in Madhya Pradesh


  1. Khajuraho Group of Monuments - Wikipedia, the free ...

    en.wikipedia.org/wiki/Khajuraho_Group_of_Monuments

    The Khajuraho Group of Monuments are a group of Hindu and Jain temples in Madhya Pradesh, India. About 620 kilometres (385 mi) southeast of New Delhi, ...






































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