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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 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him 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 29 year tenure till date Aug 2016, Around 30 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, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries...... , 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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TA 1887 a highly potent and selective hSGLT2 inhibitor

Abstract Image6a-4 is TA 1887


Figure imgf000007_0001


TA 1887


CAS  1003005-29-5

Deleted CAS Registry Numbers: 1274890-​87-​7

C24 H26 F N O5

1H-​Indole, 3-​[(4-​cyclopropylphenyl)​methyl]​-​4-​fluoro-​1-​β-​D-​glucopyranosyl-


(2R,3R,4S,5S,6R)-2-(3-(4-cvclopropylbenzyl)-4-fluoro-1 H-indol- 1 -yl)-6-(hvdroxymethyl)tetrahvdro-2H-pyran-3,4,5-triol,

(TA-1887), a highly potent and selective hSGLT2 inhibitor, with pronounced antihyperglycemic effects in high-fat diet-fed KK (HF-KK) mice. Our results suggest the potential of indole-N-glucosides as novel antihyperglycemic agents through inhibition of renal SGLT2

Mitsubishi Tanabe Pharma Corp,




Glucagon-like peptide-1 (GLP-I) is an incretin hormone that is released from L-cells in lower small intestine after food intake. GLP-I has been shown to stimulate glucose-dependent insulin secretion from pancreatic β-cells and increase pancreatic β-cell mass. GLP-I has also been shown to reduce the rate of gastric emptying and promote satiety. However, GLP-I is rapidly cleaved by dipeptidyl peptidase 4 (DPP4) leading to inactivation of its biological activity. Therefore, DPP4 inhibitors are considered to be useful as anti-diabetics or anti-obesity agents.

Sodium-glucose co-transporters (SGLTs) , primarily found in the intestine and the kidney, are a family of proteins involved in glucose absorption. Plasma glucose is filtered in the glomerulus and is reabsorbed by SGLTs in the proximal tubules. Therefore, inhibition of SGLTs cause excretion of blood glucose into urine and leads to reduction of plasma glucose level. In fact, it is confirmed that by continuous subcutaneous administration of an SGLT inhibitor, phlorizin, to diabetic animal models, the blood glucose level thereof can be normalized, and that by keeping the blood glucose level normal for a long time, the insulin secretion and insulin resistance can be improved [cf., Journal of Clinical Investigation, vol. 79, p. 1510 (1987); ibid., vol. 80, p. 1037 (1987); ibid., vol. 87, p. 561 (1991) ] .

In addition, by treating diabetic animal models with an SGLT inhibitor for a long time, insulin secretion response and insulin sensitivity of the animal models are improved without incurring any adverse affects on the kidney or imbalance in blood levels of electrolytes, and as a result, the onset and progress of diabetic nephropathy and diabetic neuropathy are prevented [cf., Journal of Medicinal Chemistry, vol. 42, p. 5311 (1999); British Journal of Pharmacology, vol. 132, p. 578 (2001)].

In view of the above, SGLT inhibitors are expected to improve insulin secretion and insulin resistance by decreasing the blood glucose level in diabetic patients and to prevent the onset and progress of diabetes mellitus and diabetic complications


DPP4 inhibitors are well known to those skilled in the art, and examples of DPP4 inhibitors can be found in the following publications: (1) TANABE SEIYAKU Co., Ltd.: WO 02/30891 or the corresponding U.S. patent (No. 6,849,622); and WO 02/30890 or the corresponding U.S. patent (No. 7,138,397); .

(2) Ferring BV: WO 95/15309, WO 01/40180, WO 01/81304, WO

01/81337, WO 03/000250, and WO 03/035057; (3) Probiodrug: WO 97/40832, EP1082314, WO 99/61431, WO

03/015775; (4) Novartis AG: WO 98/19998, WO 00/34241, WO 01/96295, US 6,107,317, US 6,110,949, and US 6,172,081;

(5) GlaxoSmithKline: WO 03/002531, WO 03/002530, and WO 03/002553; (6) Bristol Myers Squibb: WO 01/68603, WO 02/83128, and WO 2005/012249;

(7) Merck & Co.: WO 02/76450, and WO 03/004498;

(8) Srryx Inc.: WO 2005/026148, WO 2005/030751, WO 2005/095381, WO 2004/087053, and WO 2004/103993; (9) Mitsubishi Pharma Corp.: WO 02/14271, US 7,060,722, US

7,074,794, WO 2003/24942, Japan Patent Publication No.

2002-265439, Japan Patent Publication No. 2005-170792, and

WO 2006/088129;

(10) Taisho Pharma Co., Ltd.: WO 2004/020407; (12) Yamanouchi Pharmaceutical Co., Ltd.: WO 2004/009544,-

(13) Kyowa Hakko Kogyo : WO 02/051836;

(14) Kyorin Seiyaku: WO 2005/075421, WO 2005/077900, and WO 2005/082847;

(15) Alantos Pharmaceuticals: WO 2006/116157; (16) Glenmark Pharmaceuticals: WO 2006/090244, and WO 2005/075426;

(17) Sanwa Kagaku Kenkyusho : WO 2004/067509; and

(18) LG lifescience: WO 2005/037828, and WO 2006/104356.

In a preferable embodiment of the present invention, DPP4 inhibitors are the aliphatic nitrogen-containing 5- membered ring compounds disclosed in US 6,849,622, which are represented by Formula (29) :



WO 2012162115

The present invention is further directed to a process for the preparation of a compound of formula (l-S)



(also known as 3-(4-cyclopropylbenzyl)-4-fluoro-1 -p-D-glucopyranosyl- 1 /-/-indole); or a pharmaceutically acceptable salt or prodrug thereof;



reacting a compound of formula (V-S), wherein PG1 is an oxygen protecting group with an acylating reagent; wherein the acylating reagent is present in an amount in the range of from about 1 .5 to about 3.0 molar equivalents; in the presence of a carbonyl source; in a first organic solvent; at a temperature in the range of from about room temperature to about 40°C; to yield the corresponding compound of formula (Vl-S);


reacting the compound of formula (Vl-S) with a compound of formula (Vll-S), wherein A1 is MgBr or MgCI; in an anhydrous organic solvent; to yield the corresponding compound of formula (Vlll-S);


reacting the compound of formula (Vlll-S) with a reducing agent; in the presence of a Lewis acid; in a second organic solvent; to yield the

corresponding compound of formula (IX-S);


Scheme 2.


Example 1 : f2R.3R.4S.5R.6R)-2-facetoxymethyl)-6-f4-fluoro-3-formyl-1 H- indol-1 -yl)tetrahvdro-2H-pyran-3,4,5-triyl triacetate


A 5-L 4-neck round bottom flask equipped with a thermocouple controller, mechanical stirrer, addition funnel, condenser, heating mantle, and a nitrogen inlet adapter was (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-fluoro-1 H- indol-1 -yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (225.0 g, 0.459 mol), DCE (1 .5 L) and DMF (50.2 ml_, 0.643 mol). The resulting mixture was warmed to 25°C, then phosphoryl chloride (107.8 ml_, 1 .15 mol) was added slowly via an addition funnel over 75 min. The resulting mixture was stirred for 30 min after the addition was completed, then slowly warmed to 40°C over 30 min, and then agitated at 40°C for an additional 12 h. The resulting solution was slowly poured into a rapidly stirred warm (40°C) 3M aqueous NaOAc (3.0 L) solution over 45 min. After the addition was completed, CH2CI2 (4.0 L) was added and the phases were separated. The aqueous phase was back extracted with CH2CI2 (1 .0 L) and the organic phases were combined, washed with 0.05 M HCI (2.0 L) and deionized water (2.0 L), then dried over MgS04. After filtration, the solvents were concentrated to dryness in vacuo to yield a solid, which was flushed with ethanol (1 .0 L) and re-evaporated. The resulting solid was transferred into a vacuum oven and dried at 40°C for 20 h to yield the title compound as a slightly yellow-brown solid.

1 H NMR (DMSO-d6, 300 MHz) δ 10.1 (s, 1 H), 8.53 (s, 1 H), 7.66 (d, J = 7.3 Hz, 1 H), 7.38 (m, 1 H), 7.10(dd, J = 6.7, 6.9 Hz, 1 H), 6.38 (d, J = 7.5 Hz, 1 H), 5.68 (dd, J = 6.5, 6.6 Hz, 1 H), 5.56 (t, J = 7.1 Hz, 1 H), 5.32 (t, J = 7.2 Hz, 1 H) 4.41 – 4.28 (m, 1 H), 4.24 – 4.06 (m, 2 H), 2.05 (s, 3H), 2.0 (s, 3H), 1 .98 (s, 3H), 1 .64 (s, 3H) 1JC NMR (DMSO-c(6, 75.47 MHz) £183.8, 169.9, 169.5, 169.3, 168.4, 155.8, 139.2, 135.7, 124.8, 1 17.7, 1 13.1 , 108.3, 107,9, 81 .9, 73.5, 72.1 , 70.3, 67.6, 61 .9, 20.4, 20.3, 20.1 , 19.6

LC-MS mlz MH+ = 494 (MH+), 516 [M+Na]+, 1009 [2M+Na]+

[a]D 25 = -0.099 (c = 0.316, CHCI3).

Example 2: f2R.3R.4S.5R.6R)-2-facetoxymethyl)-6-f3-ff4-cvclopropyl- phenyl)(hvdroxy)methyl)-4-fluoro-1 H-indol-1 -yl)tetrahydro-2H-pyran-3,4,5- triyl triacetate


A 12-L 4-neck round bottom flask equipped with a mechanical stirrer, a thermocouple, a septum and nitrogen inlet adapter was charged with the compound prepared as in Example 1 (230 g, 0.457 mol) and anhydrous THF (4.2 L), and the resulting solution was cooled to 0°C with stirring under N2. A solution of freshly prepared (4-cyclopropylphenyl)magnesium bromide in THF (530 mL) was added dropwise via a double-tipped needle under gentle positive nitrogen pressure over 20 min, while the internal temperature was maintained between 0-8°C by adjusting the rate of addition. The resulting mixture was stirred at 0°C for 30 min. The reaction was quenched with saturated aqueous NH4CI solution (5.4 L) and then extracted with EtOAc (4 L, 3 L). The combined organic phase was washed with brine (2.7 L) and dried over MgS04. After filtration, the filtrate was concentrated at 66°C under house vacuum (-120 mmHg) followed by hi-vacuum (-20 mmHg) to yield a residue which contained a large amount of EtOAc, which residue was chased with ΟΗ2ΟΙ2 (800 mL) to yield the title compound as a yellowish solid, which was used in next step without further purification.

1 H NMR (DMSO-cfe, 300 MHz) δ 7.53 (dd, J = 7.9, 1 .1 Hz, 1 H), 7.41 (dd, J = 8.0, 1 .0 Hz, 1 H), 7.10-6.92 (m, 3 H), 6.78 (m, 1 H), 6.15 (m, 1 H), 5.92 (dd, J = 5.0, 4.1 Hz, 1 H), 5.65 (dd, J = 5.1 , 4.2 Hz, 1 H), 5.50 (m, 1 H), 5.24 (dd, J = 7.9, 8.3 Hz, 1 H), 4.38 – 4.22 (m, 1 H), 4.20-4.0 (m, 2 H), 2.05 (s, 3 H), 2.01 (s, 3 H), 1 .98 (s, 3 H), 1 .84 (m, 1 H), 0.92 (m, 2 H), 0.61 (m, 2 H)

13C NMR (DMSO-c/6, 75.47 MHz): £ 170.1 , 170.0, 169.9, 169.3, 156.1 , 140.9 139.0, 137.9, 128.0 (2 C), 125.2 (2 C), 124.2, 122.6, 1 16.3, 1 14.6, 107.4, 105.2, 81 .5, 76.8, 73.0, 72.6, 70.1 , 68.2, 62.0, 20.6, 20.4, 20.2, 19.8, 14.8, 8.96 (2 C)

LC-MS mlz MH+ = 612 (MH+), 634 [M+Na]+.

Example 3: (2R.3R.4S.5R.6R)-2-(acetoxymethyl)-6-(3-(4- cvclopropylbenzyl)-4-fluoro-1H-indol-1 -yl)tetrahvdro-2H-pyran-3,4.5-triyl triacetate




A 3-L 4-neck round bottom flask equipped with a mechanical stirrer, a thermocouple, a septum and nitrogen inlet adapter, was charged with the product prepared as in Example 2 above (82%, 334.6 g, 0.449 mol), DCE (1 .14 L), CH3CN (2.28 L), and Et3SiH (108.6 mL, 0.671 mol) and the resulting mixture was stirred and cooled to 0°C under N2. Boron trifluoride etherate (68.8 mL; 0.539 mol) was added dropwise over 10 min and the resulting mixture was stirred at 0°C for 30 minutes. After completion, saturated aqueous NaHCC>3 solution (4.2 L) was added to the mixture, which was extracted with EtOAc (5 L, 4 L) and the combined organic phase was dried over MgS04. After filtration, the filtrate was concentrated under house vacuum at 60°C to yield the title compound as a slightly yellowish solid.

The slightly yellowish solid (315.0 g) was triturated with EtOH (2.1 L, 200 proof) in a 4-L heavy duty Erlenmeyer flask at 76°C (with sonication x 3), and then gradually cooled to 20°C and stirred under N2 for 1 h. The solid was then collected by filtration and washed with cold (0°C) EtOH (200 ml_), dried by air- suction for 30 min, and then placed in a vacuum oven under house vacuum with gentle of N2 stream at 60°C for 18 h, to yield the title compound as an off- white crystalline solid.

1 H NMR (DMSO-de, 300 MHz) δ 7.47 (d, J = 8.3 Hz, 1 H), 7.22 (s, 1 H),

7.20-7.10 (m, 1 H), 7.06 (d, J = 8.1 , 2 H), 6.95 (d, J = 8.1 Hz, 1 H), 6.78 (dd, J = 7.1 , 7.0 Hz, 1 H), 6.16 (d, J = 7.1 Hz, 1 H), 5.61 -5.44 (m, 2 H), 5.21 (t, J = 7.3, 7.1 Hz, 1 H), 4.34 – 4.21 (m, 1 H), 4.18-4.04 (m, 2 H), 4.0 (s, 2 H), 2.04 (s, 3 H), 1 .97 (s, 3 H), 1 .95 (s, 3 H), 1 .84 (m, 1 H), 1 .63 (s, 3 H), 0.89 (m, 2 H), 0.61 (m, 2 H)

13C NMR (DMSO-d6, 75.47 MHz): £ 169.9, 169.5, 169.3, 168.3, 156.2, 140.9, 139.0, 137.9, 128.0 (2 C), 125.2 (2 C), 124.2, 122.7, 1 16.1 , 1 14.1 , 107.2, 105.0, 81 .7, 73.0, 72.5, 69.8, 68.0, 62.0, 31 .2, 20.4, 20.3, 20.2, 19.7, 14.6, 8.93 (2 C)

LC-MS mlz MH+ = 596 (MH+), 618 [M+Na]+, 1213 [2M+Na]+

[a]D 25 = -0.008 (c = 0.306, CHCI3).

Example 4: (2R.3R.4S.5S.6R)-2-(3-(4-cvclopropylbenzyl)-4-fluoro-1 H-indol- 1 -yl)-6-(hvdroxymethyl)tetrahvdro-2H-pyran-3,4,5-triol, ethanolate



A 12-L 4-neck round bottom flask equipped with a mechanical stirrer, a thermocouple, a septum and nitrogen inlet adapter, was charged with the compound prepared as in Example 3 above (250 g, 0.413 mol), MeOH (1 .2 L) and THF (2.4 L), and the resulting mixture was stirred at 20°C under N2.

Sodium methoxide (2.5 ml_, 0.012 mol) solution was added dropwise and the resulting mixture was stirred at 20°C for 3 h. The solvent was concentrated at 60°C under house vacuum to yield a residue, which was dissolved in EtOAc (8.0 L), washed with brine (800 mL x 2) (Note 2), and dried over MgS04. The insoluble materials were removed by filtration, and the filtrate was concentrated at 60-66°C under hi-vacuum (20 mmHg) to yield the title compound as a slightly yellowish foamy solid.

The above obtained slightly yellowish foamy solid (195.1 g) was dissolved in EtOH (900 mL) at 76°C, and deionized H20 (1800 mL) was added slowly in a small stream that resulted in a slightly yellowish clear solution, which was then gradually cooled to 40°C with stirring while seeded (wherein the seeds were prepared, for example, as described in Example 5, below). The resulting slightly white-yellowish suspension was stirred at 20°C for 20 h, the solids were collected by filtration, washed with cold (0°C) EtOH/H20 (1 :4), and dried by air-suction for 6 h with gentle stream of N2 to yield the title compound as an off-white crystalline solid, as its corresponding EtOH/H20 solvate.

The structure of the EtOH/H20 solvate was confirmed by its 1H-NMR and LC-MS analyses. 1H-NMR indicated strong H20 and EtOH solvent residues, and the EtOH residue could not be removed by drying process. In addition, p-XRD of this crystalline solid showed a different pattern than that measured for a hemi-hydrate standard.

Example 5: (2R,3R,4S,5S,6R)-2-(3-(4-cvclopropylbenzyl)-4-fluoro-1 H-indol- 1 -yl)-6-(hvdroxymethyl)tetrahvdro-2H-pyran-3,4,5-triol, ethanolate

A 500-mL 3-neck round bottom flask equipped with a mechanical stirrer was charged with the compound prepared as in Example 3 above (4.67 g, 0.00784 mol), MeOH (47 mL) and THF (93 mL), and the resulting mixture was stirred at room temperature under argon atmosphere. Sodium methoxide (catalytic amount) solution was added dropwise and the resulting mixture was stirred at room temperature for 1 h. The solvent was concentrated at 30°C under reduced pressure. The residue was purified by silica gel column chromatography (chloroform : methanol = 99 : 1 – 90 : 10) to yield a colorless foamy solid (3.17 g).

First Crystallization

A portion of the colorless foamy solid prepared as described above (0.056 g) was crystallized from EtOH/H20 (1 :9, 5mL), at room temperature, to yield the title compound, as its corresponding EtOH solvate, as colorless crystals (0.047 g).

Second Crystallization

A second portion of the colorless foamy solid prepared as described above (1 .21 g) was dissolved in EtOH (6 mL) at room temperature. H20 (6 mL) was added, followed by addition of seeds (the colorless crystals, prepared as described in the first crystallization step above). The resulting suspension was stirred at room temperature for 18 h, the solids were collected by filtration, washed with EtOH/H20 (1 :4), and dried under reduced pressure to yield the title compound t, as its corresponding EtOH solvate, as an colorless crystalline solid (0.856 g).

The structure for the isolated compound was confirmed by 1H NMR, with peaks corresponding to the compound of formula (l-S) plus ethanol. Example 6: f2R.3R.4S.5S.6R)-2-f3-f4-cvclopropylbenzyl)-4-fluoro-1H-indol- 1 -yl)-6-(hvdroxymethyl)tetrahvdro-2H-pyran-3,4,5-triol hemihydrate





A 5-L 4-neck round bottom flask equipped with a mechanical stirrer, a thermocouple, a septum and nitrogen inlet adapter was charged with the ethanolate (solvate) compound prepared as in Example 4 above (198.5 g, 0.399 mol) and deionized H20 (3.2 L). After the off-white suspension was warmed to 76°C in a hot water bath, along with sonication (x 4), it was gradually cooled to 20°C. The white suspension was stirred for 20 h at 20°C and then at 10°C for 1 h. The solid was collected by filtration, washed with deionized H20 (100 mL x 2), dried by air-suction for 2 h, and then placed in an oven under house vacuum with gentle stream of N2 at 50°C for 20 h, then at 60°C for 3 h to yield the title compound as an off-white crystalline solid.1 H NMR showed no EtOH residue and the p-XRD confirmed that the isolated material was a crystalline solid. TGA and DSC indicated that the isolated material contained about 2.3% of water (H20). M.P. = 108-1 1 1 °C.

1 H NMR (DMSO-c(6, 300 MHz) δ 7.36 (d, J = 8.2 Hz, 1 H), 7.22 (s, 1 H), 7.14 (d, J = 8.1 , 2 H), 7.10-7.0 (m, 1 H), 6.96 (d, J = 8.1 Hz, 2 H), 6.73 (dd, J = 7.5, 7.7 Hz, 1 H), 5.38 (d, J = 7.7 Hz, 1 H), 5.21 (d, J = 6.9 Hz, 1 H), 5.18 (d, J = 6.8 Hz, 1 H), 5.10 (d, J = 6.9 Hz, 1 H), 4.54 (t, J = 6.9, 1 .8 Hz, 1 H), 4.04 (s, 2 H), 3.75-3.60 (m, 2 H), 3.52-3.30 (m, 3 H), 3.20-3.17 (m, 1 H), 1 .84 (m, 1 H), 0.89 (m, 2 H), 0.61 (m, 2 H)

13C NMR (DMSO-de, 75.47 MHz): £ 156.2, 140.8, 139.4, 138.2, 128.2 (2 C), 125.2 (2 C), 124.4, 121 .8, 1 15.9, 1 12.8, 107.4, 104.2, 84.8, 79.3, 77.4, 71 .7, 69.8, 60.8, 31 .3, 14.6, 8.92 (2 C) LC-MS mlz MH+ = 428 (MH+), 450 [M+Na]+, 877 [2M+Na]+

[a]D 25 = -0.026 (c = 0.302, CH3OH)

Elemental Analysis: C2 H26NF05 + 0.54 H20 (MW = 437.20):

Theory: %C, 65.93; %H, 6.24; %N, 3.20; %F, 4.35, %H20, %2.23. Found: %C, 65.66; %H, 6.16; %N, 3.05; %F, 4.18, %H20, %2.26.



JP 2009196984


WO 2008013322

Scheme 1 :

( III ) (ID


Scheme 2 :


( In the above scheme , R4 is bromine , or iodine , and the other symbols are the same as defined above.


The starting compounds of formula (V) can be prepared in accordance with the following scheme:


(V) (In the above scheme, the symbols are the same as defined above. )

The compounds of formula (XII ) can be prepared in accordance with the following scheme :


(In the above scheme, R5 is alkyl, and the other symbols are the same as defined above.)

Example 1 :

3- (4-Cyclopropylphenylmethyl) -4-fluoro-1- (β-D-gluco- pyranosyl) indole


(1) A mixture of 4-fluoroindoline (185 mg) and D-glucose (267 mg) in H2O (0.74 ml) – ethyl alcohol (9 ml) was refluxed under argon atmosphere for 24 hours. The solvent was evaporated under reduced pressure to give crude 4-fluoro-1- (β-D-glucopyranosyl) indoline, whichwas used in the subsequent step without furtherpurification.

(2) The above compound was suspended in chloroform (8 ml) , and thereto were added successively pyridine (0.873 ml), acetic anhydride (1.02 ml) and 4- (dimethylamino) pyridine (a catalytic amount) . After being stirred at room temperature for 21 hours, the reaction solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate , and the solution was washed witha 10 % aqueous copper (II) sulfate solutiontwice anda saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 90 : 10 – 60 : 40) to give 4-fluoro-1- (2, 3, 4, 6- tetra-O-acetyl-β-D-glucopyranosyl) indoline (365 mg) as colorless amorphous. APCI-Mass m/Z 468 (M+H) . 1H-NMR (DMSO-d6) δ 1.93 (s, 3H) , 1.96 (S1 3H) , 1.97 (s, 3H) , 2.00 (s, 3H) , 2.83 (ddd, J = 15.5, 10.5 and 10.3 Hz, IH) , 2.99 – 3.05 (m, IH) , 3.49 – 3.57 (m, 2H), 3.95 – 3.99 (m, IH), 4.07 – 4.11 (m, 2H), 4.95 (t, J = 9.5 Hz, IH) , 5.15 (t, J = 9.4 Hz, IH) , 5.42 (t, J= 9.6Hz, IH) , 5.49 (d, J= 9.3 Hz, IH) , 6.48 (t, J = 8.6 Hz, IH) , 6.60 (d, J = 8.0 Hz, IH) , 7.05 – 7.10 (m, IH) .

(3) The above compound (348 mg) was dissolved in 1,4-dioxane (14 ml), and thereto was added 2, 3-dichloro-5, 6-dicyano-l, 4- benzoquinone (306 mg) . After being stirred at room temperature for 33 hours , thereto was added a saturated aqueous sodium hydrogen carbonate solution (20 ml) , and the organic solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate twice, and the combinedorganic layerwas washedwithbrine, dried over magnesium sulfate and treated with activated carbon. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 90 : 10 – 60 : 40) and recrystallization from ethyl alcohol to give 4-fluoro-1- (2,3,4, 6-tetra-O-acetyl-β-D-glucopyranosyl) indole (313 mg) as colorless crystals, mp 132-135°C. APCI-Mass m/Z 483 (M+NH4) . 1H-NMR (DMSO-d6) δ 1.64 (s, 3H), 1.97 (s, 3H), 1.99 (s, 3H), 2.04 (S, 3H), 4.10 (ABX, J = 12.4, 2.7 Hz, IH), 4.14 (ABX, J = 12.4, 5.2 Hz, IH) , 4.31 (ddd, J = 10.0, 5.2 and 2.7 Hz, IH) , 5.25 (t, J = 9.7 Hz, IH) , 5.53 (t, J = 9.5 Hz, IH) , 5.61 (t, J = 9.3 Hz, IH) , 6.22 (d, J = 9.0 Hz, IH) , 6.58 (d, J = 3.4 Hz, IH) , 6.88 (dd, J = 10.8, 7.9 Hz, IH) , 7.19 (td, J = 8.1, 5.3 Hz, IH) , 7.51 (d, J = 8.5 Hz, IH) , 7.53 (d, J = 3.4 Hz, IH) . (4) The above compound (3.50 g) and N, N-dimethylformamide (3.49 ml) were dissolved in 1, 2-dichloroethane (70 ml) , and thereto was added dropwise phosphorus (III) oxychloride (2.10 ml) . The mixture was stirred at 7O0C for 1 hour, and thereto was added water (100 ml) at 00C. The resultant mixture was extracted with ethyl acetate (200 ml) twice, and the combined organic layer was washed with brine (40 ml) and dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 90 : 10 – 50 : 50) and recrystallization from ethyl alcohol (20 ml) to give

4-fluoro-1- (2,3,4, 6-tetra-O-acetyl-β-D-glucopyranosyl) – indole-3 -carboxaldehyde (2.93 g) as colorless crystals, tnp 190 – 192°C. APCI-Mass m/Z 511 (M+NH4) . 1H-NMR (DMSO-de) δ 1.64 (s,

3H), 1.98 (s, 3H), 2.00 (s, 3H), 2.05 (s, 3H), 4.12 (A part of

ABX, J = 12.4, 2.5 Hz, IH) , 4.17 (B part of ABX, «7 = 12.4, 5.5

Hz, IH) , 4.33 (ddd, J= 10.0, 5.5 and 2.5 Hz, IH) , 5.32 (t, J= 9.8 Hz, IH) , 5.56 (t, J = 9.6 Hz, IH) , 5.66 (t, J = 9.3 Hz, IH) ,

6.36 (d, J = 9.0 Hz, IH) , 7.11 (dd, J = 10.6, 8.0 Hz, IH) , 7.38

(td, J = 8.1, 5.1 Hz, IH) , 7.65 (d, J = 8.3 Hz, IH) , 8.53 (s, IH) ,

10.0 (d, J = 2.9 Hz, IH) .

(5) To a mixture of magnesium turnings (664 mg) and 1, 2-dibromoethane (one drop) in tetrahydrofuran (40 ml) was added dropwise a solution of l-bromo-4-cyclopropylbenzene (see WO 96/07657) (5.2Ig) in tetrahydrofuran (12 ml) over 25 minutes under being stirred vigorously, and the mixture was vigorously stirred for 30 minutes at room temperature. The resultant mixture was then dropwise added to a solution of the above 4-fluoro-1- (2 , 3 , 4, 6- tetra-O-acetyl-β-D-glucopyranosyl) indole-3 -carboxaldehyde (4.35 g) in tetrahydrofuran (130 ml) over 15 minutes at -780C under argon atmosphere . The mixture was stirred at same temperature for 30 minutes, and thereto was added a saturated aqueous ammonium chloride solution (200 ml) . The resultant mixture was extracted with ethyl acetate (150 ml) twice, and the combined organic layer was dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure to give crude 4-cyclopropylphenyl 4-fluoro-l- (2,3,4, 6-tetra-O-acetyl-β-D-glucopyranosyl) indol-3-yl methanol, which was used in the subsequent step without further purification.

(6) To a stirred solution of the above compound and triethylsilane (2.11 ml) in dichloromethane (44 ml) – acetonitrile (87 ml) was added boron trifluoride -diethyl ether complex (1.34 ml) at O0C under argon atmosphere . The mixture was stirred at same temperature for 20 minutes, and thereto was added a saturated aqueous sodium


m/Z 479/481 (M+NH4) . 1H-NMR (DMSO-d6) δ 0.59 – 0.62 (m, 2H) , 0.88

– 0.91 (m, 2H) , 1.83 – 1.87 (m, IH) , 3.21 – 3.50 (m, 4H) , 3.57

– 3.63 (m, IH) , 3.65 – 3.71 (m, IH) , 4.18 (s, 2H) , 4.54 (t, J = 5.5 Hz, IH) , 5.10 (d, J = 5.3 Hz, IH) , 5.16 (d, J = 5.0 Hz, IH) , 5.23 (d, J = 5.8 Hz, IH) , 5.38 (d, J = 9.0 Hz, IH) , 6.97 (d, J = 8.2 Hz, 2H) , 7.01 (dd, J = 9.4, 2.0 Hz, IH) , 7.08 (d, J = 8.0 Hz, 2H) , 7.22 (s, IH) , 7.47 (dd, J = 10.1, 2.1 Hz, IH) .



US 20110065200

Glucose analogs have long been used for the study of glucose transport and for the characterization of glucose transporters (for review, see Gatley (2003) J Nucl Med. 44(7):1082-6). Alpha-methylglucoside (AMG) is often the analog of choice for cell-based assays designed to study the activity of SGLT1 and/or SGLT2.




WO 2009091082

Figure imgf000067_0001R1 = FLUORO, R2= H




Novel Indole-N-glucoside, TA-1887 As a Sodium Glucose Cotransporter 2 Inhibitor for Treatment of Type 2 Diabetes 
(ACS Medicinal Chemistry Letters) Thursday November 21st 2013
Author(s): Sumihiro NomuraYasuo YamamotoYosuke MatsumuraKiyomi OhbaShigeki SakamakiHirotaka KimataKeiko NakayamaChiaki KuriyamaYasuaki MatsushitaKiichiro UetaMinoru Tsuda-Tsukimoto,
GO TO: [Article]


Organic Process Research & Development (2012), 16(11), 1727-1732.

Abstract Image

A practical synthesis of two N-glycoside indoles 1 and 2, identified as highly potent sodium-dependent glucose transporter (SGLT) inhibitors is described. Highlights of the synthetic process include a selective and quantitative Vilsmeier acylation and a high-yielding Grignard coupling reaction. The chemistry developed has been applied to prepare two separate SGLT inhibitors 1 and 2 for clinical evaluation without recourse to chromatography.

Preparation of (2R,3R,4S,5S,6R)-2-(3-(4-Cyclopropylbenzyl)-4-fluoro-1H-indol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (1)

To a solution of compound 6 (250 g, 0.413 mol) in MeOH (1.2 L) and THF (2.4 L) was added sodium methoxide (2.5 mL, 0.012 mol), ………….DELETED………………….. There was obtained 198.5 g (97.5% isolated yield based on free base form; 98.8 LCAP) of 1 EtOH/H2O solvate as an off-white crystalline solid. A slurry of the EtOH/H2O solvate 1 (198.5 g, 0.399 mol) in de-ionized H2O (3.2 L,) was warmed to 76 °C, and then the slurry was gradually cooled to 20 °C over 30 min. The white suspension was stirred at 20 °C for 20 min and then at 10 °C for 1 h. The solid was collected by filtration, washed with de-ionized H2O (100 mL × 2), dried in an oven at 50 °C for 20 h and further at 60 °C for 3 h to afford 177.4 g, (99.8% isolated yield, 98.6 LCAP) of 1 hemihydrate as an off-white crystalline solid, of which the 1H NMR showed no EtOH residue and the powder X-ray diffraction (pXRD) confirmed that it was a crystalline solid. TGA indicated it contained 2.3% of water.
Mp = 108–111 °C.
1H NMR (DMSO-d6, 300 MHz) δ 7.36 (d, J = 8.2 Hz, 1 H), 7.22 (s, 1 H), 7.14 (d, J = 8.1, 2 H), 7.10–7.0 (m, 1 H), 6.96 (d, J = 8.1 Hz, 2 H), 6.73 (dd, J = 7.5, 7.7 Hz, 1 H), 5.38 (d, J = 7.7 Hz, 1 H), 5.21 (d, J = 6.9 Hz, 1 H), 5.18 (d, J = 6.8 Hz, 1 H), 5.10 (d, J = 6.9 Hz, 1 H), 4.54 (t, J = 6.9, 1.8 Hz, 1 H), 4.04 (s, 2 H), 3.75–3.60 (m, 2 H), 3.52–3.30 (m, 3 H), 3.20–3.17 (m, 1 H), 1.84 (m, 1 H), 0.89 (m, 2 H), 0.61 (m, 2 H).
13C NMR (DMSO-d6, 75.47 MHz): δ 156.2, 140.8, 139.4, 138.2, 128.2 (2 C), 125.2 (2 C), 124.4, 121.8, 115.9, 112.8, 107.4, 104.2, 84.8, 79.3, 77.4, 71.7, 69.8, 60.8, 31.3, 14.6, 8.92 (2 C). LC–MS m/z MH+ = 428 (MH+), 450 [M + Na]+, 877 [2M + Na]+.
[α]25D = −0.026 (c = 0.302, CH3OH).
Anal. Calc’d for C24H26NFO5·0.54 H2O: C, 65.93; H, 6.24; N, 3.20; F, 4.35, H2O, 2.23. Found: C, 65.66; H, 6.16; N, 3.05; F, 4.18, H2O, 2.26.




Journal of Medicinal Chemistry (2010), 53(24), 8770-8774





Organic Process Research & Development (2012), 16(11), 1727-1732.


C32 H34 F N O9
1H-​Indole, 3-​[(4-​cyclopropylphenyl)​methyl]​-​4-​fluoro-​1-​(2,​3,​4,​6-​tetra-​O-​acetyl-​β-​D-​glucopyranosyl)​-
Preparation of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(3-(4-cyclopropylbenzyl)-4-fluoro-1H-indol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl Triacetate (6)

To a stirred solution of 5 (82%, 334.6 g, 0.449 mol) in DCE (1.14 L) and MeCN (2.28 L) at 0 °C was added Et3SiH (108.6 mL, 0.671 mol) followed by the addition of boron trifluoride etherate (68.8 mL, 0.539 mol) ———DELETE………………….. There was obtained 228.6 g (85% isolated yield, 98.4 LCAP) of pure 6 as an off-white crystalline solid. Mp 168–169 °C. 1H NMR (DMSO-d6, 300 MHz) δ 7.47 (d, J = 7.2 Hz, 1H), 7.22 (s, 1H), 7.20–7.10 (m, 1H), 7.06 (d, J = 8.1, 2H), 6.95 (d, J = 8.1 Hz, 2H), 6.78 (dd, J = 7.3, 7.0 Hz, 1H), 6.16 (d, J = 7.1 Hz, 1H), 5.61–5.48 (m, 2H), 5.21 (t, J = 7.3, 7.1 Hz, 1H), 4.34 – 4.25 (m, 1H), 4.18–4.04 (m, 2H), 4.0 (s, 2H), 2.04 (s, 3H), 1.97 (s, 3H), 1.95 (s, 3H), 1.84 (m, 1H), 1.61 (s, 3H), 0.89 (m, 2H), 0.61 (m, 2H). 13C NMR (DMSO-d6, 75.47 MHz): δ 169.9, 169.5, 169.3, 168.3, 156.2, 140.9, 139.0, 137.9, 128.0 (2 C), 125.2 (2 C), 124.2, 122.7, 116.1, 114.1, 107.2, 105.0, 81.7, 73.0, 72.5, 69.8, 68.0, 62.0, 31.2, 20.4, 20.3, 20.2, 19.7, 14.6, 8.93 (2 C). HRMS: m/z = 596.2261 [M – 1]+. [α]25D = −0.008 (c = 0.306, CHCl3).
WO2005012326A1 * Jul 30, 2004 Feb 10, 2005 Tanabe Seiyaku Co Novel compounds having inhibitory activity against sodium-dependant transporter
WO2010092124A1 * Feb 11, 2010 Aug 19, 2010 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising linagliptin and optionally a sglt2 inhibitor, and uses thereof
WO2010092125A1 * Feb 11, 2010 Aug 19, 2010 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof
WO2011143296A1 * May 11, 2011 Nov 17, 2011 Janssen Pharmaceutica Nv Pharmaceutical formulations comprising 1 – (beta-d-glucopyranosyl) – 2 -thienylmethylbenzene derivatives as inhibitors of sglt
US8163704 Oct 18, 2010 Apr 24, 2012 Novartis Ag Glycoside derivatives and uses thereof
US8466114 Mar 21, 2012 Jun 18, 2013 Novartis Ag Glycoside derivatives and uses thereof
WO2009091082A1 * Jan 16, 2009 Jul 23, 2009 Mitsubishi Tanabe Pharma Corp Combination therapy comprising sglt inhibitors and dpp4 inhibitors
WO2009117421A2 * Mar 17, 2009 Sep 24, 2009 Kalypsys, Inc. Heterocyclic modulators of gpr119 for treatment of disease
WO2011048148A2 Oct 20, 2010 Apr 28, 2011 Novartis Ag Glycoside derivative and uses thereof
WO2012089633A1 * Dec 22, 2011 Jul 5, 2012 Sanofi Novel pyrimidine derivatives, preparation thereof, and pharmaceutical use thereof as akt(pkb) phosphorylation inhibitors
WO2012162113A1 * May 18, 2012 Nov 29, 2012 Janssen Pharmaceutica Nv Process for the preparation of compounds useful as inhibittors of sglt-2
WO2012162115A2 * May 18, 2012 Nov 29, 2012 Janssen Pharmaceutica Nv Process for the preparation of compounds useful as inhibitors of sglt-2
WO2013090550A1 * Dec 13, 2012 Jun 20, 2013 National Health Research Institutes Novel glycoside compounds
US7666845 Dec 3, 2007 Feb 23, 2010 Janssen Pharmaceutica N.V. Compounds having inhibitory activity against sodium-dependent glucose transporter
US8394772 Oct 20, 2010 Mar 12, 2013 Novartis Ag Glycoside derivative and uses thereof
US8697658 Dec 13, 2012 Apr 15, 2014 National Health Research Institutes Glycoside compounds

FDA grants breakthrough therapy designation to Boehringer’s Idarucizumab, BI 655075

  • 1-​225-​Immunoglobulin G1, anti-​(dabigatran) (human-​Mus musculus γ1-​chain) (225→219′)​-​disulfide with immunoglobulin G1, anti-​(dabigatran) (human-​Mus musculus κ-​chain)Protein SequenceSequence Length: 444, 225, 219

BI 655075, Idarucizumab

  • Idarucizumab [INN]
  • UNII-97RWB5S1U6

 CAS 1362509-93-0

Treatment of dabigatran associated haemorrhage


The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for Boehringer Ingelheim Pharmaceuticals’ idarucizumab, an investigational fully humanised antibody fragment being studied as a specific antidote for Pradaxa.
Boehringer Ingelheim Pharmaceuticals Medicine & Regulatory Affairs senior vice-president Sabine Luik said: “We are committed to innovative research and to advancing care in patients taking Pradaxa.

  1. IDARUCIZUMAB (BI 655075)
    • What is it?  It is a humanized antibody fragment directed against dabigatran; generated from mouse monoclonal antibody against dabigatran; humanized and reduced to a FAb fragment.
    • What anticoagulant drugs might it reverse?  Dabigatran.
    • Clinical trial status:  (a) A phase 3 study of patients on dabigatran with major bleeding or needing emergency surgery is in the planning stages and will likely start in 2014. (b) A phase 1 study to determine the effect of idarucizumab on coagulation tests in dabigatran-treated healthy volunteers has been completed (NCT01688830), another two are ongoing (NCT01955720; NCT02028780).

Pradaxa Antidote, Idarucizumab Designated Breakthrough Therapy

Boehringer Ingelheim announced that the FDA has granted Breakthrough Therapy designation to idarucizumab, an investigational fully humanized antibody fragment (Fab), being evaluated as a specific antidote for Pradaxa (dabigatran etexilate mesylate).

Data from a Phase 1 trial demonstrated that idarucizumab was able to achieve immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy humans. The on-set of action of the antidote was detected immediately following a 5-minute infusion while thrombin time was reversed with idarucizumab. Reversal of the anticoagulation effect was complete and sustained in 7 of 9 subjects who received the 2g dose and in 8 out of 8 subjects who received the 4g dose. The 1g dose resulted in complete reversal of anticoagulation effect; however, after approximately 30 minutes there was some return of the anticoagulation effects of dabigatran.

RELATED: Anticoagulant Dosing Conversions

A global Phase 3 study, RE-VERSE AD, is underway in patients taking Pradaxa who have uncontrolled bleeding or require emergency surgery or procedures. Currently there are no specific antidotes for newer oral anticoagulants.

Pradaxa is approved to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation (AF). Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with parenteral anticoagulant for 5–10 days. To reduce risk of recurrent DVT/PE in patients who have been previously treated.

For more information call (800) 542-6257 or visit

P/0069/2014: European Medicines Agency decision of 17 March 2014 on the agreement of apaediatric investigation plan and on the granting of a deferral for idarucizumab (EMEA-001438-PIP01-13)



FDA approves Alcobra’s protocol for Phase IIb study of metadoxine drug candidate

The salt pyridoxine-pyrrolidone carboxylate.png



Alcobra Ltd.


Israel-based Alcobra has received approval from the US Food and Drug Administration (FDA) for its protocol for planned Phase IIb clinical study of Metadoxine Extended Release (MDX) drug candidate for the treatment of Fragile X Syndrome.



The multi-center, randomized, placebo-controlled, Phase IIb study, will be conducted primarily in the US and patient enrollment is expected to begin in the near future.

The study is supported by data collected from multiple earlier pre-clinical studies which demonstrated significant improvement in behavioral and cognitive outcomes based on evaluations of memory, learning, and social interaction.



Metadoxine, or Pyridoxol L-2-pyrrolidone-5-carboxylate, whose structure formula is reported hereinbelow


is known for its effectiveness in acute and chronic alcoholism and for the prevention of alcohol related pathology



The salt pyridoxine-pyrrolidone carboxylate.png
Systematic (IUPAC) name
L-Proline, 5-oxo-, compd. with 5-hydroxy-6-methylpyridine-3,4-dimethanol (1:1)
Clinical data
Legal status PHASE 2
Routes Oral, IV
CAS number 0074536-44-0
ATC code N07BB
Chemical data
Formula C13H18N2O6 
Mol. mass 298 g/mol


Metadoxine, also known as pyridoxine-pyrrolidone carboxylate, is a drug used to treat chronic and acute alcohol abuse.[1] Metadoxine improved the clinical signs of acute alcohol intoxication and accelerated alcohol clearance from the blood [2]It is presently in human clinical trials as an attention-deficit/hyperactivity disorder predominantly inattentive treatment.[3]

Pyridoxine is one form of vitamin B6 and a precursor to the metabolically active pyridoxal phosphate. Pyridoxal phosphate is a coenzyme to many enzymes: see vitamin B6 metabolic functions.

Pyrrolidone carboxylate is involved in amino acid metabolism through the glutathione pathway.[4] Glutathione is an important antioxidant and combats redox imbalance. It also supports de novo ATP synthesis.[5]

Alcohol-induced liver diseases are a common disorder in modern communities and societies. For example, in Europe there are more than 45 million individuals showing signs of alcohol-related damage such as liver disease and myopathies. Chronic alcohol consumption increases hepatic accumulation of triglycerides and leads to hepatic steatosis, which is the earliest and most common response to severe alcohol intoxication.

Thus, severe alcohol intoxication is a serious disease that should be treated with medication in order to reduce the damage to the human body of the alcohol intoxicated individual. For example, alcohol intoxication can be treated with metadoxine (pyridoxine L-2-pyrrolidone-5-carboxylate). Metadoxine is a salt of the corresponding anion of L-2-pyrrolidone-5-carboxylic acid (L-2-pyroglutamic acid) (1) and the protonated derivative of pyridoxine (vitamin B6) (2), having the following structures:

(1) (2)

WO 2008/066353 discloses the use of Metadoxine in the treatment of alcohol intoxication either alone or in combination with other active agents. WO 2008/066353 mentions that metadoxine does not inhibit the expression and activation of an alcohol-induced cytochrome P450 2El, which is the key enzyme involved in alcohol-induced toxicity. Thus, the use of metadoxine may be limited.


Several studies have shown that in order to effectively treat alcohol intoxication, there is a need for a relatively high daily dose (ca. 900 mg) administered intravenously (see, e.g., Lu et al. Chin. Med. J. 2007, 120 (2), 155-168 and Shpilenya et al. Alcohol Clin. Exp. Res. 2002, 26 (3), 340-346). These studies disclose side effects associated with the use of metadoxine, including nausea and vomiting.

Thus, there exists a need in the art for effective and safe drugs for treating alcohol intoxication and other associated diseases.



Metadoxine is predominantly used in developing nations for acute alcohol intoxication. Alternate names include: Abrixone (Eurodrug, Mexico), Alcotel (Il Yang, South Korea), Ganxin (Qidu Pharmaceutical, China), Metadoxil (Baldacci, Georgia; Baldacci, Italy; Baldacci, Lithuania; CSC, Russian Federation; Eurodrug, Colombia; Eurodrug, Hungary; Eurodrug, Thailand; Micro HC, India), Viboliv (Dr. Reddy’s, India), and Xin Li De (Zhenyuan Pharm, China).[6]

Fatty liver refers to a pathogenic condition where fat comprises more than 5% of the total weight of the liver. Liver diseases including the fatty liver, hepatitis, fibrosis and cirrhosis are known to be the most serious disease next to cancer causing death in people with ages 40 to 50, in the advanced countries. In advanced countries, nearly about 30% of the population is with fatty liver, and about 20% of people with fatty liver progresses to cirrhosis. About half of the cirrhosis patients die of liver diseases within 10 years after the diagnosis. Fatty liver and steatohepatitis are frequently found in people who intake excessive alcohols and who have obesity, diabetes, hyperlipemia, etc. Among them, alcoholic steatohepatitis (ASH), which is caused by excessive alcohol intake, is at high risk of progressing to hepatitis, cirrhosis and hepatoma, along with non-alcoholic steatohepatitis (NASH).

When taken in, alcohol is carried to the liver and oxidized to acetaldehyde by such enzymes as alcohol dehydrogenase, catalase, etc. The acetaldehyde is metabolized and converted into acetate and is used as energy source. Repeated alcohol intake induces the increase of NADH and NADP+ during the metabolism and acetaldehyde which as the metabolite product of alcohol depletes GSH, thereby changing intracellular oxidation-reduction homeostasis and inducing oxidative stress. Oxidative stress may cause mitochondrial dysfunction, lipid peroxidation and protein modification, thereby leading to death of hepatocytes, inflammation, activation of astrocytes, and the like. In addition, the increase of NADH promotes lipid synthesis, thereby inducing fatty liver.

At present, there are few therapeutically effective drugs for treating fatty liver. Exercise and controlled diet are recommended, but these are not so effective in treating fatty liver. The development of an effective treatment drug is in desperate need. As it is known that fatty liver is related with insulin resistance which is found in diabetes and obesity, the therapeutic effect of some anti-diabetic drugs, e.g., metformin, on fatty liver has been reported. But, the drug has the problem that it may induce adverse reactions such as hepatotoxicity or lactic acidosis. Betaine, glucuronate, methionine, choline and lipotrophic agents are often used as alternative supplementary drug therapy, but they are not fully proven on medical or pharmaceutical basis. Accordingly, development of a fatty liver treatment having superior effect and safety with no adverse reactions is in need.

Metadoxine (pyridoxol 1-2-pyrrolidone-5-carboxylate) is a complex compound of pyridoxine and pyrrolidone carboxylate represented by the formula (1) below:



Metadoxine is a drug used to treat alcoholic liver disease. It is used to treat liver fibrosis and fatty liver through increasing alcohol metabolism and turnover, reducing toxicity of free radicals and restoring the level of ATP and glutathione (Arosio, et al., Pharmacol. Toxicol. 73: 301-304, 1993; Calabrese, et al., Int. J. Tissue React. 17: 101-108, 1995; Calabrese, et al., Drugs Exp. Clin. Res. 24: 85-91, 1998; Caballeria, et al., J. Hepatol. 28: 54-60, 1998; and Muriel, et al., Liver Int. 23: 262-268, 2003).

However, metadoxine is unable to inhibit the expression and activation of alcohol-induced cytochrome P4502E1 (CYP2E1), which is a key enzyme involved in alcohol-induced toxicity, and thus unable to control the augmentation of inflammation mediated by CYP2E1. Therefore, the treatment of alcohol-induced fatty liver using metadoxine is very limited. Further, the expression of CYP2E1 is related with insulin resistance, thus metadoxine cannot not overcome insulin resistance.

Garlic oil is a liquid including about 1% of allicin along with reduced allicin and other sulfur-containing substances. Upon binding to vitamin B1, allicin is turned into allithiamin, which is chemically stable, acts swiftly, and is easily absorbed by the digestive organs. The substance inhibits carcinogenesis induced by chemicals in white rats (Brady, et al., Cancer Res. 48: 5937-5940, 1988; and Reddy, et al., Cancer Res. 53: 3493-3498, 1993), induces phase II enzyme (Hayes, et al., Carcinogenesis 8: 1155-1157, 1987; and Sparnins, et al., Carcinogenesis 9: 131-134, 1988), and inactivates CYP2E1 (Brady, et al., Chem. Res. Toxicol. 4:642-647, 1991). In addition, garlic oil is reported to have antithrombotic, anti-atherosclerotic, antimutagenic, anticancer and antibacterial activities (Agarwal, Med. Res. Rev. 16: 111-124, 1996; and Augusti, Indian J. Exp. Biol. 34: 634-660, 1996).



Treatment for acute alcohol abuse

In an animal model, metadoxine treatment increased the clearance of alcohol and acetaldehyde, reduced the damaging effect of free radicals, and enabled cells to restore cellular ATP and glutathione levels. [7][8] It increases the urinary elimination of ketones, which are formed when the oxidation rate of acetaldehyde into acetate is exceeded on massive alcohol intoxication.[8][4]

As a medical treatment, it is typically given intravenously.

Treatment for AD/HD-PI

Metadoxine is a selective antagonist to the 5-HT2B receptor, a member of the serotonin receptor family.[3] Electrophysiological studies also showed that Metadoxine caused a dose-dependent, reversible reduction in glutamatergic excitatory transmission and enhancement of GABAergic inhibitory transmission, changes that may be associated with cognitive regulation.[3] It is given orally in an extended release pill, which differs from the instant release alcohol treatment.

Treatment for liver disease

Metadoxine may block the differentiation step of preadipocytes by inhibiting CREB phosphorylation and binding to the cAMP response element, thereby repressing CCAAT/enhancer-binding protein b during hormone-induced adipogenesis.[7]

Treatment for Fragile X Syndrome

Metadoxine treatment led to significant improvement in blood and brain biological markers (AKT and ERK), which may have a role in learning and memory.[3] The study also demonstrated a reduction in the amount of immature neurons and abnormally increased protein levels.[3]




Scheme 1


[0054] In another aspect, the invention provides methods of synthetically preparing, e.g., carboxylated lactam ring of formula (II) (e.g. wherein n=2 for a reactant of formula (IVb) in Scheme 2), carboxylated lactam ring of (III) (e.g. wherein n=3 for a reactant of formula (IVb) in Scheme 2) and carboxylated lactam ring of formula (IV) (e.g. wherein n=4 for a reactant of formula (IVb) in Scheme 2), as depicted in Scheme 2.

Scheme 2


Compound IVb, n=2,3,4

[0055] In another aspect, the invention provides methods of preparing a salt adduct including a positively charged pyridoxine moiety, or a derivative thereof, and a carboxylated 5- to 7-membered lactam ring, including the steps of:

(a) suspending an optionally substituted amino dioic acid in water and heating for a sufficient period of time to allow completing lactamization reaction;

(b) optionally decolorizing the reaction mixture to eliminate impurities;

(c) isolating the lactam carboxylate;

(d) optionally purifying the obtained lactam carboxylate by crystallization;

(e) admixing the obtained lactam carboxylate and a pyridoxine base or a derivative thereof in a solvent mixture optionally under heating; and

(f) isolating the product.

In certain embodiments, a solvent mixture of step (e) includes a mixture of an alcohol such as methanol, ethanol, isopropanol and the like, and water. [0059] According to yet another embodiment, there is provided methods of preparing N-substituted L-pyroglutamic acid and the carboxylate thereof, such as, for example, N-methyl-L-pyroglutamic acid (1-methyl-L-pyroglutamic acid), starting from L-pyroglutamic acid ethyl ester, as depicted in Scheme 3 below. Scheme 3



1-methyl-L-pyroglutamic acid

[0060] The invention further provides methods of preparing a salt adduct of the invention, wherein said positively charged moiety is a substituted pyridoxine, as depicted in Scheme 4 below. The starting reagent is 2-methyl-3-hydroxy-4- methoxymethyl-5-hydroxymethyl-pyridine hydrochloride (Compound (V)). The preparation of the corresponding salt is described in Example 1. Scheme 4

HCI NH 3 / MeOH 2 L-pyroglutamic acid

Compound V Compound Vl


Salt lid

[0061] The invention further provides methods of preparing a salt adduct of the invention, wherein said positively charged moiety is a substituted pyridoxine, as depicted in Scheme 5 below. The starting reagent in scheme 5 is 2-methyl-3-hydroxy- 4-methoxymethyl-5-hydroxymethyl-pyridine hydrochloride (Compound V). The preparation of the corresponding salt is described in Example 2. Scheme 5


Compound V


Compound VIII IX Compound L-pyroglutamic acid

, SaIt IIe

WO2010150261A1 * June 24, 2010 Dec 29, 2010 Alcobra Ltd. A method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition
WO2011061743A1 * Nov 18, 2010 May 26, 2011 Alcobra Ltd. Metadoxine and derivatives thereof for use in the treatment of inflammation and immune-related disorders
US8476304 Jul 3, 2012 Jul 2, 2013 Alcobra Ltd. Method for decreasing symptoms of alcohol consumption
US8710067 Jul 3, 2012 Apr 29, 2014 Alcobra Ltd. Method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition
WO2008066353A1 * Nov 30, 2007 June 5, 2008 Jae Hoon Choi Pharmaceutical composition comprising metadoxine and garlic oil for preventing and treating alcohol-induced fatty liver and steatohepatitis
WO2009004629A2 * Jul 3, 2008 Jan 8, 2009 Alcobra Ltd A method for decreasing symptoms of alcohol consumption
FR2172906A1 * Title not available
US4313952 * Dec 8, 1980 Feb 2, 1982 Maximum Baldacci Method of treating acute alcoholic intoxication with pyridoxine P.C.A.


  1. Addolorato, G; Ancona C, Capristo E, Gasbarrini G (2003). “Metadoxine in the treatment of acute and chronic alcoholism: a review”. International Journal of Immunopathology and Pharmacology.
  2. Martinez, Diaz; Villamil Salcedo; Cruz Fuentes (2001). “Efficacy of Metadoxine in the Management of Acute Alcohol Intoxication”. Journal of International Medical Research.
  3. “Metadoxine extended release (MDX) for adult ADHD” (in English). Alcobra Ltd. 2014. Retrieved 2014-05-07.
  4. Shpilenya, Leonid S.; Alexander P. Muzychenko; Giovanni Gasbarrini; Giovanni Addolorato (2002). “Metadoxine in Acute Alcohol Intoxication: A Double-Blind, Randomized, Placebo-Controlled Study”. Alcoholism:Clinical and Experimental Research.
  5. Shull, Kenneth H.; Robert Kisilevsky (1996). “Effects of Metadoxine on cellular status of glutathione and on enzymetric defence system following acute ethanol intoxication in rats”. Drugs Exp Clin Res.
  6. “Metadoxine –” (in English). 2014. Retrieved 2014-05-08.
  7. Yang, YM; HE Kim; SH Ki; SG Kim (2009). “Metadoxine, an ion-pair of pyridoxine and L-2-pyrrolidone-5-carboxylate, blocks adipocyte differentiation in association with inhibition of the PKA-CREB pathway.”. Archives of Biochemistry and Biophysics.
  8. Calabrese, V; A Calderone; N Ragusa; V Rizza (1971). “Effects of l-2-pyrrolidone-5-carboxylate on hepatic adenosine triphosphate levels in the ethionine-treated rat”. Biochemical Pharmacology.

Zuo Jin Wan Chinese Herbal Formula Found Helpful in Gastric (Stomach) Cancer

Lyra Nara Blog

Gastric (Stomach) cancer is a particularly deadly form of cancer that has a very poor prognosis in most cases.  Worldwide over 700,000 people will die from stomach cancer and less than 10% of the people diagnosed with stomach cancer will survive.  Because of these statistics, researchers are continually looking for anything that can provide a better outcome.

Recently a team of researchers from Shanghai University conducted a study exploring a traditional Chinese Herbal Formula called Zuo Jin Wan on stomach cancer cells.  The formula itself is quite basic compared to many in the materia medica with only two ingredients -Huang Lian and Whu Zhu Yu (ina  6:1 ratio).  In TCM it is primarily used for what we would call liver fire leading to rebellious qi – which in some cases could be rephrase so to speak as poor diet and emotional stress leading to reflux.

Within the study, which is very heavy on biochemical terms…

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Laser Used to Deliver Dopamine in Hope for Parkinson’s Treatment

Lyra Nara Blog

laser for drug delivery Laser Used to Deliver Dopamine in Hope for Parkinsons Treatment

In people suffering from Parkinson’s, errors of metabolism in dopaminergic neurons of substantia nigra play an important role in pathophysiology of the disease. One of the functions of dopamine is in helping control muscle movement. Unfortunately, simply injecting Parkinson’s patients with dopamine does not cure the disease, since the chemical needs to be delivered in precise quantities over extended time period just where it’s needed. To help with that, researchers at Okinawa Institute of Science and Technology, Japan and University of Otago, New Zealand have developed a method of encapsulating dopamine within liposomes that can then be released using a femtosecond laser.

These liposomes are spherical structures made of fat cells that are very stable when inside the human body. They are able to ferry their cargo throughout the body, which will only interact with cells and tissues when the liposomes are ruptured by some external force. The researchers utilized…

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Oregon State University Researchers Build Novel Sepsis Filter

Lyra Nara Blog

sepsis device Oregon State University Researchers Build Novel Sepsis Filter

Researchers at Oregon State University have engineered a special filter that may be capable of clearing blood of endotoxins that play important role in sepsis. The National Science Foundation just awarded $200,000 to the team to further develop the device for clinical use.

Unlike antibiotics, the filter actually removes bacteria and endotoxins instead of just killing the bacteria and leaving particulates and vasoactive substances to circulate in the body. It’s about the size of a mug and has a bunch of microchannels about the diameter of human hair that are coated on the inside with so-called “pendant polymer brushes.” These are chains of carbon and oxygen that are attached to the filter like microscopic hairs that prevent coagulation and have peptides on their tips to grab onto the endotoxins. The researchers plan to make the device cheap to manufacture by moving to low-cost polymers as the main material, and then pressing toward clinical…

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The effect of catch-up growth by various diets and resveratrol intervention on bone status


09 Mar 2012

Although many current studies focused on catch up growth (CUG) have described its high susceptibility to insulin resistance-related diseases very few have focused on the effect of CUG on bone metabolism, especially in adulthood. As diet is a controllable factor, the influence of re-feeding with different dietary patterns on bone parameters is important to study. Resveratrol has been attributed a number of beneficial effects in mammals including osteotrophic properties. In the March 2012 issue of Experimental Biology and Medicine Wang and colleagues describe the first study to describe the effects of CUG, with different diets, on bone status and the role of resveratrol in CUG models.

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GSK 2263167 a S1P1 receptor agonist

Abstract Image

gsk 2262167

CAS,  1165924-28-6 FREE FORM

1165923-54-5 NA SALT

1458576-13-0  MONOHYDRATE

Glaxo Group Ltd,


C25 H26 N4 O4



2(1H)​-​ Isoquinolinepropanoi​c acid, 6-​[5-​[3-​cyano-​4-​(1-​methylethoxy)​phenyl]​-​1,​2,​4-​oxadiazol-​3-​ yl]​-​3,​4-​dihydro-​5-​methyl-

3-[6-(5-{3-Cyano-4-[(1 -methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl- 3,4-dihydro-2(1H)-isoquinolinyl]propanoic acid


Sphingosine 1 -phosphate (S1 P) is a bioactive lipid mediator formed by the phosphorylation of sphingosine by sphingosine kinases and is found in high levels in the blood. It is produced and secreted by a number of cell types, including those of hematopoietic origin such as platelets and mast cells (Okamoto et al 1998 J Biol Chem 273(42):27104; Sanchez and HIa 2004, J Cell Biochem 92:913). It has a wide range of biological actions, including regulation of cell proliferation, differentiation, motility, vascularisation, and activation of inflammatory cells and platelets (Pyne and Pyne 2000, Biochem J. 349: 385). Five subtypes of S1 P responsive receptor have been described, S1 P1 (Edg-1 ), S1 P2 (Edg-5), S1 P3 (Edg-3), S1 P4 (Edg-6), and S1 P5 (Edg-8), forming part of the G-protein coupled endothelial differentiation gene family of receptors (Chun et al 2002 Pharmacological Reviews 54:265, Sanchez and HIa 2004 J Cellular Biochemistry, 92:913). These 5 receptors show differential mRNA expression, with S1 P1-3 being widely expressed, S1 P4 expressed on lymphoid and hematopoietic tissues and S1 P5 primarily in brain and to a lower degree in spleen. They signal via different subsets of G proteins to promote a variety of biological responses (Kluk and HIa 2002 Biochem et Biophysica Acta 1582:72, Sanchez and HIa 2004, J Cellular Biochem 92:913).

Proposed roles for the S1 P1 receptor include lymphocyte trafficking, cytokine induction/suppression and effects on endothelial cells (Rosen and Goetzl 2005 Nat Rev Immunol. 5:560). Agonists of the S1 P1 receptor have been used in a number of autoimmune and transplantation animal models, including Experimental Autoimmune Encephalomelitis (EAE) models of MS, to reduce the severity of the induced disease (Brinkman et al 2003 JBC 277:21453; Fujino et al 2003 J Pharmacol Exp Ther 305:70; Webb et al 2004 J Neuroimmunol 153:108; Rausch et al 2004 J Magn Reson Imaging 20:16). This activity is reported to be mediated by the effect of S1 P1 agonists on lymphocyte circulation through the lymph system. Treatment with S1 P1 agonists results in the sequestration of lymphocytes within secondary lymphoid organs such as the lymph nodes, inducing a reversible peripheral lymphopoenia in animal models (Chiba et al 1998, J Immunology 160:5037, Forrest et al 2004 J Pharmacol Exp Ther 309:758; Sanna et al 2004 JBC 279:13839). Published data on agonists suggests that compound treatment induces loss of the S1 P1 receptor from the cell surface via internalisation (Graler and Goetzl 2004 FASEB J 18:551 ; Matloubian et al 2004 Nature 427:355; Jo et al 2005 Chem Biol 12:703) and it is this reduction of S1 P1 receptor on immune cells which contributes to the reduction of movement of T cells from the lymph nodes back into the blood stream.

S1 P1 gene deletion causes embryonic lethality. Experiments to examine the role of the S1 P1 receptor in lymphocyte migration and trafficking have included the adoptive transfer of labelled S1 P1 deficient T cells into irradiated wild type mice. These cells showed a reduced egress from secondary lymphoid organs (Matloubian et al 2004 Nature 427:355).

S1 P1 has also been ascribed a role in endothelial cell junction modulation (Allende et al 2003 102:3665, Blood Singelton et al 2005 FASEB J 19:1646). With respect to this endothelial action, S1 P1 agonists have been reported to have an effect on isolated lymph nodes which may be contributing to a role in modulating immune disorders. S1 P1 agonists caused a closing of the endothelial stromal ‘gates’ of lymphatic sinuses which drain the lymph nodes and prevent lymphocyte egress (Wei wt al 2005, Nat. Immunology 6:1228).

The immunosuppressive compound FTY720 (JP1 1080026-A) has been shown to reduce circulating lymphocytes in animals and man, have disease modulating activity in animal models of immune disorders and reduce remission rates in relapsing remitting Multiple Sclerosis (Brinkman et al 2002 JBC 277:21453, Mandala et al 2002 Science 296:346, Fujino et al 2003 J Pharmacology and Experimental Therapeutics 305:45658, Brinkman et al 2004 American J Transplantation 4:1019, Webb et al

2004 J Neuroimmunology 153:108, Morris et al 2005 EurJ Immunol 35:3570, Chiba

2005 Pharmacology and Therapeutics 108:308, Kahan et al 2003, Transplantation 76:1079, Kappos et al 2006 New Eng J Medicine 335:1124). This compound is a prodrug that is phosphorylated in vivo by sphingosine kinases to give a molecule that has agonist activity at the S1 P1 , S1 P3, S1 P4 and S1 P5 receptors. Clinical studies have demonstrated that treatment with FTY720 results in bradycardia in the first 24 hours of treatment (Kappos et al 2006 New Eng J Medicine 335:1124). The bradycardia is thought to be due to agonism at the S1 P3 receptor, based on a number of cell based and animal experiments. These include the use of S1 P3 knock- out animals which, unlike wild type mice, do not demonstrate bradycardia following FTY720 administration and the use of S1 P1 selective compounds (Hale et al 2004 Bioorganic & Medicinal Chemistry Letters 14:3501 , Sanna et al 2004 JBC 279:13839, Koyrakh et al 2005 American J Transplantation 5:529).

Hence, there is a need for S1 P1 receptor agonist compounds with selectivity over S1 P3 which might be expected to show a reduced tendency to induce bradycardia.

The following patent applications describe oxadiazole derivatives as S1 P1 agonists: WO03/105771 , WO05/058848, WO06/047195, WO06/100633, WO06/115188, WO06/131336, WO07/024922 and WO07/1 16866.

The following patent applications describe tetrahydroisoquinolinyl-oxadiazole derivatives as S1 P receptor agonists: WO06/064757, WO06/001463, WO04/1 13330.


Figure CN103251950AC00031

Figure CN103251950AC00041

Figure CN103251950AC00051





Abstract Image

Organic Process Research & Development (2013), 17(10), 1239-1246.

Chemical Development, GlaxoSmithKline Research and Development Ltd., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
Org. Process Res. Dev.201317 (10), pp 1239–1246
DOI: 10.1021/op400162p

A fit for purpose approach has been adopted in order to develop a robust, scalable route to the S1P1 receptor agonist, GSK2263167. The key steps include a Robinson ring annulation followed by a Saegusa oxidation, providing rapid access to an advanced phenol intermediate. Despite the use of stoichiometric palladium acetate for the Saegusa oxidation, near complete recovery of the palladium has been demonstrated. The remaining steps have been optimised including the removal of all chromatography. An alternative to the Saegusa oxidation is described as well as the development of a flow process to facilitate further scale-up of the amidoxime preparation using hydroxylamine at elevated temperature.



Will watson

WILL WATSON in  ACS noteworthy chemistry wrote

Researchers make a profit from a pilot plant reaction. R. H. Harris and co-workers at GlaxoSmithKline Research and Development (Stevenage, UK) developed a “fit-for-purpose” method for scaling up the synthesis of a sphingosine 1-phosphate receptor agonist. They shortened the route to the 5-hydroxytetrahydroisoquinoline intermediate from eight to two steps by carrying out a Robinson annulation on N-Boc-4-piperidone followed by aromatization of the cyclohexane ring. (Boc is tert-butoxycarbonyl.)

The authors found, however, that only a Saegusa oxidation that uses stoichiometric quantities of Pd(OAc)2 catalyst gives good conversion in the aromatization. Optimizing the workup by adding HCO2K at the end of the reaction to reduce the Pd(II) and precipitate the palladium as Pd(0) made it possible to recover 10.3 kg of the 10.5kg of palladium used in the pilot plant.

The price of palladium doubled during the campaign, so GlaxoSmithKline sold the palladium back to supplier Johnson Matthey at a profit of UK£62,500. Subsequently, the authors developed a more economical CuBr2-mediated aromatization reaction. (Org. Process Res. Dev. 2013, 17, 1239–1246Will Watson)


ACS Medicinal Chemistry Letters (2011), 2(6), 444-449.


Abstract Image


Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P1 and S1P3−5). It has been postulated that fingolimod’s efficacy is due to S1P1 agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P3 agonism. We have discovered a series of selective S1P1 agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate, 20, a potent, S1P3-sparing, orally active S1P1 agonist. Compound20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P3 is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.

Discovery of a Selective S1P1 Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate

Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science,GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom
ACS Med. Chem. Lett.20112 (6), pp 444–449
DOI: 10.1021/ml2000214

Journal of Medicinal Chemistry (2011), 54(19), 6724-6733

Discovery of a Brain-Penetrant S1P3-Sparing Direct Agonist of the S1P1 and S1P5 Receptors Efficacious at Low Oral Dose

Immuno Inflammation Center of Excellence for Drug Discovery, Platform Technology and Science, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom
Neurology Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom
J. Med. Chem., 2011, 54 (19), pp 6724–6733
DOI: 10.1021/jm200609t
Publication Date (Web): August 15, 2011
Copyright © 2011 American Chemical Society
Telephone: + 44 1438 764319. Fax: + 44 1438 768302. E-mail:


Abstract Image


2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (Fingolimod, FTY720, Figure 1)(1) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Administration of 1 leads to the sequestration of lymphocytes in secondary lymphoid organs and consequently to a reduction of lymphocyte count in the peripheral blood. 1 is phosphorylated in vivo by sphingosine kinase-2(2, 3) to form FTY720-P 2, a potent agonist of four of the five G-protein-coupled receptors (S1P1, S1P3–5) associated with the lysolipid sphingosine 1-phosphate (S1P) 3. Agonism of the S1P1 receptor by S1P is required to induce egress of T cells from lymphoid organs and 2 acts as a functional antagonist by internalizing the receptor.(4, 5) The cardiovascular side effects observed in treated patients (bradycardia and hypertension) have been linked to partial agonism of the S1P3 receptor,(6, 7) although more recent findings from human studies indicate that S1P1 may mediate the transient effects on heart rate.(8) Owing to its lipophilic nature, 1 is able to cross the blood-brain barrier (BBB)(9) where 2 interacts with S1P receptors present on astrocytes (S1P1) and on oligodendrocytes (S1P5). Recent publications suggest this may play a role in fingolimod’s efficacy in the treatment of patients with RRMS.(10, 11)
Excellent (>1000 fold) selectivity over S1P3 can be achieved with agonists such as AMG 369(15)6 or PF-991(16)7, but these molecules, as our own S1P3-sparing agonist 8(17) (Table 1), are zwitterions and are therefore likely to have poor CNS penetration. (18) Typically, in our hands, 8 proved to be a P-gp substrate (with an efflux ratio in a human MDR1 transfected MDCK type 2 cell line of 0.5 and 6.0 in the presence and absence of a P-gp inhibitor, respectively). Interestingly, 8 shows no activity at S1P2 and S1P4, and is a partial agonist of the S1P5 receptor with similar potency to that at S1P1.(19)
Table 1. Activity of 2 and 8 at S1P1-5 Receptors

pEC50 (maximum activation %)
human receptor (assay)a 2b 8
S1P1 (β-arrestin) 7.7 (99), n = 44 8.25 (94), n = 13
S1P2 (yeast) <4.5, n = 5 <4.48 (01), n = 6
S1P3 (GTPγS) 8.3 (62), n = 38 <4.5 (35), n = 6
S1P4 (aequorin) 6.7 (48), n = 2 <4.38 (03), n = 4
S1P5 (aequorin) 7.2 (62), n = 2 6.79 (77), n = 6

See the Supporting Information for details.


For comparative published values, see ref 35.


WO 2009080724

Example 11

2-[(1 -Methylethyl)oxy]-5-[3-(5-methyl-1 ,2,3,4-tetrahydro-6-isoquinolinyl)-1 ,2,4- oxadiazol-5-yl]benzonitrile trifluoroacetic acid salt


Trifluoroacetic acid (3ml) was added to an ice cooled solution of 1 ,1-dimethylethyl 6- (5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro- 2(1 H)-isoquinolinecarboxylate (Preparation 22; 486mg, 1.02mmol) in dichloromethane (3ml). The reaction mixture was stirred at O0C for 30 minutes. The solvent was evaporated and the residue co-evaporated from toluene (x2). Trituration of the residue with diethyl ether gave the title compound as a colourless solid which was filtered off and dried (485mg). 1H NMR (400 MHz, CDCI3) δ: 1.48 (6H, d), 2.54 (3H, s), 3.09 (2H, m), 3.5 (2H, obscured by residual solvent), 4.36 (2H, s), 4.80 (1 H, m), 7.08-7.15 (2H, m), 7.85 (1 H, d), 8.33 (1 H, d), 8.42 (1 H, s), 10.20 (2H, br s). MS m/z 375 [MH]+.


Example 13 3-[6-(5-{3-Cyano-4-[(1 -methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)-5-methyl- 3,4-dihydro-2(1H)-isoquinolinyl]propanoic acid sodium salt


2M sodium hydroxide (2ml) was added to a solution of ethyl 3-[6-(5-{3-cyano-4-[(1- methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1 H)- isoquinolinyl]propanoate (Preparation 24; 80mg, 0.17mmol) in ethanol (2ml) at 6O0C. The reaction mixture was stirred at 6O0C for 2 hours, cooled to room temperature and diluted with water (2ml). The solid was filtered off, washed with a small amount of water and dried to give the title compound as a colourless solid (55mg). 1H NMR (400 MHz, deDMSO) δ: 1.39 (6H, d), 2.08 (2H, t), 2.44 (3H, s), 2.59-2.78 (6H, m), 3.56 (2H, s), 4.98 (1 H, m), 7.09 (1 H, d), 7.55 (1 H, d), 7.65 (1 H, d), 8.40 (1 H, dd), 8.50 (1 H, s). MS m/z 447 [MH]+.




CN 103251950



WO 2010146105

Preparation 12

6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride



To a solution of 1 ,1-dimethylethyl 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4- oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (1.85g, 3.8 mmol, WO 2009080724) in 1 ,4-dioxane (10ml) at room temperature under nitrogen was added slowly hydrogen chloride in 1 ,4-dioxane (4N, 30ml, 120 mmol) and the resulting mixture was stirred at room temperature for 3.5h. Removal of the solvent and co-evaporation of the residue with diethyl ether gave 6-(5-{3-chloro-4-[(1- methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)-5-methyl-1 ,2,3,4-tetrahydroisoquinoline hydrochloride (1.65g, 103%) as a white solid. LCMS (Method HpH): Retention time 1.43min, MH+ = 384

Preparation 25

2-[(1 -Methylethyl)oxy]-5-[3-(5-methyl-1 ,2,3,4-tetrahydro-6-isoquinolinyl)-1 ,2,4- oxadiazol-5-yl]benzonitrile hydrochloride

To a solution of 1 ,1-dimethylethyl 6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4- oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (Preparation 24) (3.4g, 7.2 mmol) in 1 ,4-dioxane (20ml) at room temperature under nitrogen was added a hydrogen chloride in 1 ,4-dioxane (4M, 17.9ml, 72 mmol) and the resulting mixture was stirred at this temperature for 5.5h, stored in a freezer overnight and then concentrated. The residue was co-evaporated with diethyl ether to give 2-[(1- methylethyl)oxy]-5-[3-(5-methyl-1 ,2,3,4-tetrahydro-6-isoquinolinyl)-1 ,2,4-oxadiazol-5- yl]benzonitrile hydrochloride (2.88g, 98%) as a white solid. LCMS (Method HpH): Retention time 1.21 min, MH+ = 375


Preparation 25: alternative procedure

2-[(1 -Methylethyl)oxy]-5-[3-(5-methyl-1 ,2,3,4-tetrahydro-6-isoquinolinyl)-1 ,2,4- oxadiazol-5-yl]benzonitrile trifluoroacetate


Trifluoroacetic acid (15ml) was added to an ice cooled solution of 1 ,1-dimethylethyl 6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)-5-methyl-3,4- dihydro-2(1 H)-isoquinolinecarboxylate (Preparation 24) (2.9g, 6.1 mmol) in DCM (20ml). The reaction mixture was stirred at 00C for 1 h and the solvent evaporated. The residue was co-evaporated with toluene (x2) and triturated with diethyl ether. The solid was isolated by filtration and washed with diethyl ether to give 2-[(1- methylethyl)oxy]-5-[3-(5-methyl-1 ,2,3,4-tetrahydro-6-isoquinolinyl)-1 ,2,4-oxadiazol-5- yl]benzonitrile trifluoroacetate (2.7g, 90%) as a colourless solid. LCMS (Method formate): Retention time 0.90min, MH+ = 375

1 H NMR (D6-DMSO): δH 9.16(2H, bs), 8.51 ,(1 H, d), 8.40(1 H, dd), 7.78(1 H, d), 7.57(1 H, d), 7.29(1 H, d), 4.98(1 H, m), 4.38(2H, s), 3.49(2H, partially obscured by water), 2.99(2H, t), 2.47(3H, s), 1.39(6H, d).

Preparation 25: alternative procedure

2-[(1 -methylethyl)oxy]-5-[3-(5-methyl-1 ,2,3,4-tetrahydro-6-isoquinolinyl)-1 ,2,4- oxadiazol-5-yl]benzonitrile hydrochloride


1 ,1-Dimethylethyl 6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)- 5-methyl-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (Preparation 24) (50.Og, 1 10 mmol) in DCM (150ml) was added drop-wise to hydrogen chloride in 1 ,4-dioxane (4M, 263ml, 1 100 mmol) and the mixture was stirred for 2h at room temperature, giving a pale yellow suspension. The mixture was diluted with diethyl ether (500ml), stirred for 20min. Then solid was isolated by filtration, washed with diethyl ether (3x 100ml) and dried in vacuo at 55°C overnight to give 2-[(1-methylethyl)oxy]-5-[3-(5- methyl-1 ,2,3,4-tetrahydro-6-isoquinolinyl)-1 ,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (39.8g, 92%) as white solid.

LCMS (Method HpH): Retention time 1.22min, MH+ = 375

1 H NMR (D6-DMSO) includes: δH 9.49(2H, bs), 8.51 (1 H, d), 8.40(1 H, dd), 7.77(1 H, d), 7.56(1 H, d), 7.29(1 H, d), 4.98(1 H, m), 4.35(2H, m), 3.44-3.36(2H, largely obscured by water), 3.00(2H, t), 2.47(3H, s), 1.39(6H, d).


Preparation 27

3-[6-(5-{3-Cyano-4-[(1 -methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl- 3,4-dihydro-2(1H)-isoquinolinyl]propanoic acid sodium salt


Sodium hydroxide (2M, 1 ml) was added to a stirred solution of ethyl 3-[6-(5-{3-cyano- 4-[(1-methylethyl)oxy]phenyl}-1 !2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1 H)- isoquinolinyl]propanoate (Preparation 26) (200mg, 0.42 mmol) in ethanol (1 ml). The reaction mixture was stirred at 500C for 1 h then cooled and the ethanol evaporated. The residue was diluted with water (2ml) and stirred for 15min. The precipitate was isolated by filtration, washed with water and dried under vacuum to give 3-[6-(5-{3- cyano-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro- 2(1 H)-isoquinolinyl]propanoic acid sodium salt (150mg, 76%) as a colourless solid. LCMS (Method formate): Retention time 0.92min, MH+ = 447



Xenobiotica (2012), 42(7), 671-686

  • Martini, S.; Peters, H.; Böhler, T.; Budde, K.Current Perspectives on FTY720 Expert Opin. Invest. Drugs 2007, 16, 505518

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    Billich, A.; Bornancin, F.; Dévay, P.; Mechtcheriakova, D.; Urtz, N.; Baumruker, T.Phosphorylation of the Immunomodulatory Drug FTY720 by Sphingosine Kinases J. Biol. Chem. 2003, 278, 4740847415

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    Albert, R.; Hinterding, K.; Brinkmann, V.; Guerini, D.; Müller-Hartwieg, C.; Knecht, H.; Simeon, C.; Streiff, M.; Wagner, T.; Welzenbach, K.; Zécri, F.; Zollinger, M.; Cooke, N.; Francotte, E.Novel Immunomodulator FTY720 Is Phosphorylated in Rats and Humans to Form a Single Stereoisomer. Identification, Chemical Proof, and Biological Characterisation of the Biologically Active Species and Its Enantiomer J. Med. Chem. 2005, 48, 53735377

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    Matloubian, M.; Lo, C. G.; Cinamon, G.; Lesneski, M. J.; Xu, Y.; Brinkmann, V.; Allende, M. L.; Proia, R. L.; Cyster, J. G.Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1 Nature 2004, 427, 355360

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    Wei, S. H.; Rosen, H.; Matheu, M. P.; Sanna, M. G.; Wang, S.-K.; Jo, E.; Wong, C.-H.; Parker, I.; Cahalan, M. D.Sphingosine 1-Phosphate Type 1 receptor Agonism Inhibits Transendothelial Migration of Medullary T Cells to Lymphatic Sinuses Nat. Immunol. 2005, 6, 12281235

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    Forrest, M.; Sun, S.-Y.; Hajdu, R.; Bergstrom, J.; Card, D.; Doherty, G.; Hale, J.; Keohane, C.; Meyers, C.; Milligan, J.; Mills, S.; Nomura, N.; Rosen, H.; Rosenbach, M.; Shei, G.-J.; Singer, I. I.; Tian, M.; West, S.; White, V.; Xie, J.; Proia, R. L.; Mandala, S.Immune Cell Regulation and Cardiovascular Effects of Sphingosine 1-Phosphate Receptor Agonists in Rodents Are Mediated via Distinct Receptor Subtypes J. Pharmacol. Exp. Ther. 2004, 309, 758768

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    Sanna, M. G.; Liao, J.; Jo, E.; Alfonso, C.; Ahn, M.-Y.; Peterson, M. S.; Webb, B.; Lefebvre, S.; Chun, J.; Gray, N.; Rosen, H.Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate J. Biol. Chem. 2004, 279, 1383913848

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    Gergely, P.; Wallström, E.; Nuesslein-Hildesheim, B.; Bruns, C.; Zécri, F.; Cooke, N.; Traebert, M.; Tuntland, T.; Rosenberg, M.; Saltzman, M.Phase I study with selective S1P1/S1P5 receptor modulator BAF312 indicates that S1P1 rather than S1P3 mediates transient heart rate reduction in humans Mult. Scler. 2009, 15, S31S150

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    Meno-Tetang, G. M. L.; Li, H.; Mis, S.; Pyszczynski, N.; Heining, P.; Lowe, P.; Jusko, W. J.Physiologically based pharmacokinetic modeling of FTY720 (2-amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) in rats after oral and intravenous doses Drug Metab. Dispos. 2006, 34, 14801487

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    Brinkmann, V.FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system Br. J. Pharmacol. 2009, 158, 11731182

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    Noguchi, K.; Chun, J.Roles for lysophospholipid S1P receptors in multiple sclerosis Crit. Rev. Biochem. Mol. Biol. 2011, 46, 210

2010146105A1 Jun 17, 2010 Dec 23, 2010 Glaxo Group Limited S1p1 agonists comprising a bicyclic n-containing ring
US8222245 Dec 19, 2008 Jul 17, 2012 Glaxo Group Limited Oxadiazole derivatives active on sphingosine-1-phosphate (S1P)
US8263620 Dec 19, 2008 Sep 11, 2012 Glaxo Group Limited Oxadiazole derivatives active on sphingosine-1-phosphate (SIP)
US8329730 Apr 29, 2009 Dec 11, 2012 Glaxo Group Limited Compounds


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(S)-Sitagliptin……….Synfacts by Thieme

For description see at synfacts

Contributor: Philip Kocienski

Philip Kocienski, Professor of Organic Chemistry.


Bao H, Bayeh L, Tambar UK * The University of Texas Southwestern Medical Center at Dallas, USA
Catalytic Enantioselective Allylic Amination of Olefins for the Synthesis of ent-Sitagliptin.

Synlett 2013;
24: 2459-2463



P. J. Kocienski
School of Chemistry
University of Leeds
Leeds LS2 9JT, UK

Philip J. Kocienski was born in Troy, New York, in 1946. His love for organic chemsitry, amply stimulated by Alfred Viola whilst an undergraduate at Northeastern University, was further developed at Brown University, where he obtained his PhD degree in 1971 under Joseph Ciabattoni. Postdoctoral study with George Büchi at MIT and later with Basil Lythgoe at Leeds University, England, confirmed his interest in the synthesis of natural products. He was appointed Brotherton Research lecturer at Leeds in 1979 and Professor of Chemistry at Southampton University in 1985. In 1990 he was appointed Glaxo Professor of Chemistry at Southampton University. He moved to the University of Glasgow in 1997, where he was Regius Professor of Chemistry and now he is a Professor of Chemistry at Leeds University.

In addition to Prof. Kocienski’s work as an author he is also a member of the SYNTHESIS Editorial Board and contributes greatly to the development of Thieme Chemistry’s journals

Furthermore, Prof. Kocienski has also contributed to the Science of Synthesis project where he was an author for Volume 4, Compounds of Group 15 (As, Sb, Bi) and Silicon Compounds.

Prof. Kocienski is also responsible for compiling a database called Synthesis Reviews. This resource is free and contains 16,257 English review articles (from journals and books) of interest to synthetic organic chemists. It covers literature from 1970 to 2002.



ситаглиптин [Russian]
سيتاغليبتين [Arabic]
西格列汀 [Chinese]




GREENING UP DRUGS Merck process chemists redesigned and significantly shortened the original synthesis of type 2 diabetes drug candidate sitagliptin (Januvia) to include an unprecedented efficient hydrogenation of an unprotected enamine.

MERCK was selected for the award in the greener synthetic pathways category for revising the synthesis for sitagliptin, a chiral β-amino acid derivative that is the active ingredient in Januvia, the company’s pending new treatment for type 2 diabetes. The breakthrough leading to the new synthesis was the discovery that the amino group of the key enamine intermediate doesn’t need to be protected prior to enantioselective catalytic hydrogenation of the double bond.

This development has solved a long-standing problem in the synthesis of β-amino acid derivatives, which are known for their pharmacological properties and are commonly used as chiral building blocks, noted Karl B. Hansen, a Merck process chemist involved with the synthetic effort. The outcome has been to slash the number of reaction steps in the sitagliptin synthesis from eight to three, leading to an equally dramatic reduction in the amount of chemicals and solvent needed and the amount of waste generated.

Merck’s first-generation synthesis of sitagliptin involved preparing a β-hydroxy carboxylic acid, which was converted to a protected β-lactam and then coupled to a triazole building block. Deprotecting the resulting intermediate provided the β-amino acid moiety, and sitagliptin was isolated as a phosphoric acid salt.

This synthesis involved a roundabout route involving four steps to introduce the pivotal chiral amino group of sitagliptin. The synthesis worked well to prepare more than 100 kg of the compound for clinical trials, and with modifications it was deemed to be a viable though not very green manufacturing process, Hansen pointed out. For example, the original synthesis required a number of distillations and aqueous extractions to isolate intermediates, leading to a large volume of waste to treat.

“Being environmentally friendly and economically savvy can, and does, go hand-in-hand.”

Merck process chemists recognized that a much more efficient process was possible by synthesizing the β-amino acid portion of the molecule directly from an enamine. But the protection-deprotection of the amine nitrogen with an acyl group during the hydrogenation is difficult on a large scale, and unprotected reactions generally result in lower yields and lower enantiomeric excesses, Hansen said.

Undaunted, the Merck scientists working on the revised synthesis discovered that the amino group could be efficiently introduced by an unprotected hydrogenation using a rhodium catalyst with a ferrocenyl phosphine ligand named Josiphos (C&EN, Sept. 5, 2005, page 40). Merck turned to Solvias, a Swiss company with experience in asymmetric hydrogenations that manufactures Josiphos, as a partner to help speed up the process development.

The new synthesis involves first coupling trifluorophenyl acetic acid and triazole building blocks to form a diketoamide, which in turn is converted to the enamine. This sequence is carried out without isolating intermediates. The enamine is then hydrogenated, sitagliptin is isolated and recrystallized as the phosphoric acid salt, and the rhodium Josiphos catalyst is recovered.

In sum, the revised synthesis increases the overall yield of sitagliptin by nearly 50% and reduces the amount of waste by more than 80%. A key difference is that the original synthesis produced more than 60 L of aqueous waste per kg of product, while the new synthesis completely eliminates aqueous waste. When tallied up, Merck expects these savings will prevent formation of 150,000 metric tons of solid and aqueous process waste over the lifetime of Januvia. Industry analysts speculate that regulatory approval of the drug will come by early next year and that it’s destined to become a top-selling drug.

The novel enamine hydrogenation “is arguably the most efficient means to prepare β-amino acid derivatives,” noted R. P. (Skip) Volante, Merck’s vice president of process research. The company currently is using the procedure to make several other exploratory drug candidates, he added. Overall, the redesigned synthesis of sitagliptin “is a green chemistry solution to the preparation of a challenging synthetic target and is an excellent example of a scientific innovation resulting in benefits to the environment,” Volante said.


First generation route to sitagliptin. BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; EDC = N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride; DIAD = di-isopropyl azodicarboxylate; NMM = N-methylmorpholine……..!divAbstract


First Generation Process for the Preparation of the DPP-IV Inhibitor Sitagliptin

Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065, U.S.A.
Org. Process Res. Dev., 2005, 9 (5), pp 634–639
DOI: 10.1021/op0500786
Abstract Image

A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor and potential new treatment for type II diabetes, suitable for the preparation of multi-kilogram quantities is presented. The triazolopyrazine fragment of sitagliptin was prepared in 26% yield over four chemical steps using a synthetic strategy similar to the medicinal chemistry synthesis. Key process developments were made in the first step of this sequence, the addition of hydrazine to chloropyrazine, to ensure its safe operation on a large scale. The beta-amino acid fragment of sitagliptin was prepared by asymmetric reduction of the corresponding beta-ketoester followed by a two-step elaboration to an N-benzyloxy beta-lactam. Hydrolysis of the lactam followed by direct coupling to the triazolopiperazine afforded sitagliptin after cleavage of the N-benzyloxy group and salt formation. The overall yield was 52% over eight steps.




The synthesis of 1 was completed using a four-step through-process (Scheme 4). Lactam 5 or ester 13 was hydrolyzed to amino acid 2b with LiOH18 in THF/water by either stirring at room temperature or, in the case of 13, heating to 40 °C. While the benzyloxy group of 2b could be cleaved by hydrogenation and then protected with Boc2O to prevent side reactions during the coupling to triazole 3, the benzyloxy group of 2b was found to sufficiently protect the amino group to allow the desired amide to be formed. Thus, triazole 3 was coupled to2b at 0 °C using EDC−HCl and N-methylmorpholine (NMM) as base to afford 14in >99% assay yield. Following an aqueous workup, the organic extracts were distilled into ethanol and the solution was subjected to hydrogenation with 10% Pd on carbon. The presence of water in the hydrogenation was found to be crucial to the reaction success; anhydrous solutions of 14 hydrogenated with dry Pd on carbon proceeded only to low levels of conversion to 1, and addition of water to these reductions resulted in restored performance of the catalyst. Following hydrogenation, the catalyst was removed by filtration to provide an ethanol solution of 1. Sitagliptin was isolated in >99.5% purity as its anhydrous phosphoric acid salt by crystallizing from aqueous ethanol.


Scott D Edmondson, Michael H Fisher,Dooseop Kim, Malcolm Maccoss, Emma R Parmee, Ann E Weber, Jinyou Xu


Sitagliptin phosphate monohydrate, a dipeptidyl-peptidase IV inhibitor, is marketed by Merck & Co. for the once-daily oral treatment of type 2 diabetes. The product was first launched in Mexico followed by commercialization in the U.S. The compound has also been filed for approval in the U.S. as adjunct to diet and exercise and in combination with other therapies to improve glycemic control in the treatment of diabetes. In 2007, the product was approved by the European Medicines Evaluation Agency (EMEA) and is currently available in the U.K., Germany and Spain. In 2009, sitagliptin phosphate monohydrate was approved and launched in Japan. The product is also available in Japan for the treatment of type 2 diabetes in combination with alpha-glucosidase inhibitors and in combination therapy with insulin. In 2012, the company filed for approval in Japan for the treatment of type 2 diabetes in patients with severe renal dysfunction, and in 2013 obtained the approval.

Sitagliptin phosphate monohydrate boasts a much lower risk of hypoglycemia than currently available insulin-inducing products due to its novel mechanism of action. MSD KK (formed in 2010 following the merger of Banyu and Schering-Plough KK) and Ono are developing the drug candidate in Japan. In 2008, the compound was licensed to Almirall by Merck Sharp & Dohme for comarketing in Spain for the treatment of type 2 diabetes. In 2010, FAES obtained a comarketing and commercialization license from Merck Sharp & Dohme in Spain for the treatment of type 2 diabetes.

Januvia (sitagliptin phosphate) is an antihyperglycaemic drug containing an orally active inhibitor of the dipeptidyl peptidase-IV (DPP-IV) enzyme. Developed by Merck Sharp & Dohme (MSD), a UK subsidiary of Merck & Co, sitagliptin is used for treating type 2 diabetes mellitus. The drug has proved effective in lowering blood sugar levels of diabetes patients when taken alone or in combination with other oral diabetes medications such as metformin and thiazolidinedione.

Sitagliptin was approved by the US Food and Drug Administration (FDA) in October 2006 and is marketed under the brand name Januvia in the US. Sitagliptin in combination with metformin was approved by the FDA in March 2007 and is marketed as Janumet in the US. In the EU, Januvia was approved in April 2007 and Janumet was approved in July 2008.

Sitagliptin is a triazolopiperazine based inhibitor of DPP-IV, which was discovered by
Merck. It is a potent (IC50= 18 nM) and highly selective over DPP-8 (48000 nM), DPP-9
(>100000 nM) and other isozymes.[16] It enhances the pancreatic β-cell functions, fasting and
post-prandial glycemic control in type 2 diabetic patients. In the crystal structure with DPP-IV,
unlike other substrate-based DPP-IV inhibitors, the binding orientation of the amide carbonyl of
sitagliptin is reversed, i.e. the aromatic trifluorophenyl moiety occupies S1 pocket and the β-
amino amide moiety fits into S2 pockets. The amino group forms a salt bridge and hydrogen
bonding interactions with Glu205 and Glu206, and Tyr662, respectively.The triazolopiperazinemoiety occupies the S2 extended pocket and stacks against Phe357. The exhibited binding
interactions of the trifluoromethyl group with the Arg358 and Ser209 are responsible for its high
selectivity profile. The presence of the trifluoromethyl group in the triazole ring also improves
the oral bioavailability in animal models. Sitagliptin inhibited the plasma DPP-IV up to 80% and
47% at 2 and 24 h, respectively, after a single dose of 25.0 mg in a dose-dependent manner. In a
24-week study, sitagliptin significantly decreased fasting glucose levels and HbA1c levels
(0.8%) at doses of 100 mg q.d. Thus, sitagliptin is well tolerated and body weight neutral. It is
the first DPP-IV inhibitor in the class approved by USFDA in 2006 and is used as either a
monotherapy or in combination with metformin








In the first synthetic approach, the synthesis of sitagliptin was started with the reaction of a Schollkopf reagent 6 with 2,4,5-trifluorobenzyl bromide to afford the compound 7, which was converted to compound 9 via hydrolysis of ester 8. The resulting Boc-protected amino acid 9 was converted to diazoketone 11 through mix anhydride protocol by using diazomethane. The intermediate 11 was converted to desired β-amino acid 12 by sonication in the presence of silver benzoate.[21] The sitagliptin (14) was synthesized by coupling of β-amino acid 12 with triazolopiperazine intermediate 5 followed by Boc deprotection of amino group of 13, and its corresponding hemi fumarate salt was then prepared (Scheme 1).[16]



The second approach for synthesis of sitagliptinwas started from asymmetric reduction of β-ketoester 15 using the (S)-BinapRuCl2 complex with a catalytic amount of HBr in methanol followed by hydrolysis afforded the β-hydroxy acid 16. Lactam 17 was synthesized by coupling of 16 with BnONH2 •HCl using N-(3- dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC), followed by cyclization reaction with diisopropyl azodicarboxylate (DIAD) and PPh3 . [22] Treatment of a catalytic amount of 0.1% NaOH with lactam 17 hydrolyzed and directly afforded the β-amino acid 18. This wascoupled withtriazolopiperazine 5 using EDC•HCl and N-methylmorpholine to provide the N-benzyloxy protected compound 19, which after hydrogenation using Pd/C and by consequent treatment with phosphoric acid provided the phosphate salt of sitagliptin (14) (Scheme 2).



The third approach towards the synthesis of sitagliptin is outlined in scheme 3. Meldrum adduct 22 (Hunig’s base salt) was synthesized from trifluorophenylacetic acid 20 by the formation of a mixed anhydride with pivaloyl chloride in the presence of Meldrum’s acid 21, DIPEA and catalytic amount of dimethylamino pyridine (DMAP) in acetonitrile. Treatment of 22 with TFA resulted compound 23. β-keto amide 24 was formed on reaction of 23 with triazolopiperazine 5. β-keto amide 24 on treatment with ammonium acetate in methanol formed a key intermediate, dehydrositagliptin 25 (enamine amide). This intermediate contains the entire structure of sitagliptin 14 except two hydrogen atoms. Thus, sitagliptin 14 was synthesized by enantioselective hydrogenation of dehydrositagliptin 25 in the presence of [Rh(COD)2 OTf] 12,13 and t Bu JOSIPHOS in excellent yield with 95% ee.[23,24]


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.









Vapourtec…..Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen VAPOURTEC POST

Philip R D Murray 1
Duncan L Browne 1
Julio C Pastre 1,2
Chris Butters 3
Duncan Guthrie 3
Steven V Ley 1

1 Department of Chemistry, University of Cambridge, UK
2 Instituto de Quí­mica, University of Campinas, Brazil
3 Vapourtec Ltd, UK

A new enabling-technology for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents and DIBAL-H is reported, which utilizes a newly developed chemically-resistant peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal-halogen exchange, addition, addition-elimination, conjugate addition and partial reduction are reported, along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances and examples are demonstrated over periods of several hours, to generate multi-gram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-Tamoxifen using continuous-flow organometallic reagent mediated transformations………..


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