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Structure of gemigliptin (LC15-0444).svg

GEMIGLIPTIN

1-[2(S)-Amino-4-[2,4-bis(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-yl]-4-oxobutyl]-5,5-difluoropiperidin-2-one

PHASE 3, DPP-IV inhibitor, Lg Life Sciences Ltd.

CAS 911637-19-9

Mol. Formula:   C18H19F8N5O2

Mol. Weight:489.36

Gemigliptin (rINN), previously identified as LC15-0444, is an oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs.[1] It is well known that glucose lowering effects of DPP-4 inhibitors are mainly mediated by GLP-1 and gastric inhibitory polypeptide (GIP) incretin hormones which are inactivated by DPP-4.

Gemigliptin was initially developed solely by LG Life Sciences. In 2010, Double-Crane Pharmaceutical Co. (DCPC) joined with LGLS to co-develop the final compound and collaborate on the marketing of the drug in China. LGLS also announced on Nov., 2010 that NOBEL Ilac has been granted rights to develop and commercialize gemigliptin in Turkey.

Gemigliptin, a dipeptidyl peptidase IV (CD26; DPP-IV; DP-IV) inhibitor, is currently undergoing phase III clinical trials at LG Life Sciences as an oral treatment for type II diabetes. The company is also testing the compound in phase II/III clinical studies for the treatment of patients with cisplatin-induced acute kidney injury.

DPP IV inhibitors have glucose-lowering effects mediated by GLP-1 incretin hormone which is inactivated by DPP IV. In 2010, gemigliptin was licensed to Beijing Double-Crane Pharmaceutical by LG Life Sciences for distribution and supply in China for the treatment of type 2 diabetes.

New Drug Application (NDA) for gemigliptin in the treatment of type 2 diabetes was submitted to the Korea Food & Drug Administration (KFDA) in July 2011. Then on June 27, 2012, the KFDA has approved the manufacture and distribution of LG Life Sciences’ diabetes treatment, Zemiglo, the main substance of which is gemigliptin. Clinical trials for evaluating the safety and efficacy of gemigliptin in combination with metformin have been completed.

…………

Efficient synthesis of gemigliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus, has been developed. Gemigliptin were prepared from two key API starting materials, DP18 and DP57, in 75~80% yield and >99% purity over three steps under the GMP control: coupling, deprotection of N-Boc group, and final crystallization with L-tartaric acid. All steps were conducted in the same solvent system and the intermediates were isolated by simple filtration without distillation of solvent. The established process was validated obviously through the three consecutive batches for a commercial production.

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(3S)-3-amino-4-(5,5-difluoro-2-oxopiperidino)-1-[2,4-di(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-yl]butan-1-one
Clinical data
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 94% (rat), 73% (dog), 26% (monkey)
Biological half-life 3.6 h (rat), 5.2 h (dog), 5.4 h (monkey)
Identifiers
CAS Registry Number 911637-19-9 
ATC code A10BH06
PubChem CID: 11953153
ChemSpider 10127461 Yes
UNII 5DHU18M5D6 
Synonyms LC15-0444
Chemical data
Formula C18H19F8N5O2
Molecular mass 489.36 g/mol

……………….

History

The NDA for gemigliptin was submitted to KFDA in July, 2011 and it was approved on June 27, 2012. By the end of 2012, gemigliptin will be marketed in Korea as Zemiglo which is the fifth new DPP-4 inhibitor diabetes treatment in the world.

Mechanism of action

DPP-4 is a serine protease located on the cell surfaces throughout the body. In plasma, DPP-4 enzyme rapidly inactivates incretins including GLP-1 and GIP which are produced in the intestine depending on the blood glucose level and contribute to the physiological regulation of glucose homeostatis. Active GLP-1 and GIP increase the production and release of insulin by pancreatinc beta cells. GLP-1 also reduces the scretion of glucacon by pancreatic alpha cells, thereby resulting in a decreased hepatic glucose production. However these incretins are rapidly cleaved by DPP-4 and their effects last only for a few minutes. DPP-4 inhibitors block the cleavage of the gliptins and thus lead to an increasee insulin level and a reduced glucagon level in a glucose-dependent way. This results in a decrease of fasting and postprandial glycemia, as well as HbA1c levels.[2]

Preclinical studies

Gemigliptin is a competitive, reversible DPP-4 inhibitor (IC50 = 16 nM) with excellent selectivity over other critical human proteases such as DPP-2, DPP-8DPP-9elastase,trypsinurokinase and cathepsin G. Gemigliptin was rapidly absorbed after single oral dosing and the compound was eliminated with a half-life of 3.6 h, 5.2 h, and 5.4 h in the rat, dog, and monkey, respectively.

The bioavailability of gemigliptin in the rat, dog, and monkey was species-dependent with the values of 94%, 73%, and 26%, respectively. Following the oral administration of gemigliptin in the rat, dog and monkey, about 80% inhibition of plasma DPP-4 activity were observed at the plasma levels of 18 nM, 14 nM and 4 nM, respectively.

In the diet-induced obese (DIO) mice, gemigliptin reduced glucose excursion during OGTT in a dose dependent manner with the minimum effective dose of 0.3 mg/kg and enhanced glucose-stimulated plasma GLP-1 increase in a dose dependent manner reaching the maximum effect at the dose of 1 mg/kg.

Following 4 week oral repeat dosing in the DIO mice, gemigliptin reduced significantly HbA1c with the minimum effective dose of 3 mg/kg. In the beagle dog, gemigliptin significantly enhanced active GLP-1, decreased glucagon, and reduced glucose excursion during OGTT following a single dosing.

Studies on animals suggest its positive effect on hepatic and renal fibrosis .[3][4] Data on human patients are still inconclusive .[5]

Clinical studies

The dose-range finding phase 2 study was performed and 145 patients (91men and 54 women) with type 2 diabetes mellitus were enrolled. All three doses (50,100 and 200 mg groups) of gemigliptin significantly reduced the HbA1c from baseline compared to the placebo group without a significant difference between the doses.

Subjects with a higher baseline HbA1c (≥8.5%) had a greater reduction in HbA1c. Insulin secretory function, as assessed using homeostasis model assessment-beta cell, C-peptide and the insulinogenic index, improved significantly with gemigliptin treatment. Insulin sensitivity, as assessed using homeostasis model assessment-insulin resistance, also improved significantly after 12 weeks of treatment.

The 50 and 200 mg groups had significantly reduced total cholesterol and low-density lipoprotein cholesterol levels at 12 weeks compared to the placebo group.

The incidences of adverse events were similar in all study subjects. Gemigliptin monotherapy (50 mg for 12 weeks) improved the HbA1cFPG level, oral glucose tolerance testresults, β-cell function and insulin sensitivity measures, and was well tolerated in subjects with type 2 diabetes.

Results of Phase 3 clinical trials which have been finished recently will be updated near future.

…………..

WO 2006104356

 http://www.google.co.in/patents/WO2006104356A1?cl=en

EXAMPLE 83: Synthesis of l-(f2SV2-amino-4-r2.4-bisftrifluoromethylV5.8-dihvdropyridor3.4-d]pyrimidin-7f6H)

-yl1-4-oxobutyll-5.5-difluoropiperidin-2-one [1960]

Figure imgf000147_0001

[1961] 21 mg of the title compound was obtained in a yield of 56% at the same manner as in EXAMPLE 1, except that 42 mg (0.071 mmol) of t-butyl

{(lS)-3-[2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl]-l-[(5,5

-difluoro-2-oxpiperidin-l-yl)methyl]-3-oxpropyl}carbamate obtained in

PREPARATION 143 was used. [1962] 1K NMR (CD3OD) δ 5.05-4.92 (2H, m), 3.98-3.91 (2H, m), 3.85-3.79 (2H, m),

3.70-3.59 (2H, m), 3.54-3.48 (IH, m), 3.36-3.33 (2H, m), 3.24 (IH, bra), 3.14 (IH, bra), 2.83-2.76 (IH, m), 2.72-2.53 (3H, m), 2.43-2.34 (2H, m) [1963] Mass (m/e) 490 (M+l)

[1964]

[1965] PREPARATION 144: Synthesis of t-butyl

(riSV3-r2.4-bisrtrifluoromethylV5.8-dihvdropyridor3.4-d]pyrimidin-7r6HVyl]-l-(rr2 S)-2-methyl-5-oxomorpholin-4-yl1methyl 1 -3-oxpropyl 1 carbamate

[1966] 14 mg of the title compound was obtained in a yield of 17% at the same manner as in PREPARATION 45, except that 43.7 mg (0.138 mmol) of (3S)-3-[(t-butoxycarbonyl)amino]-4-[2(S)-2-methyl-5-oxomoφholin-4-yl]-butanoic acid obtained in PREPARATION 55 and 42.5 mg (0.138 mmol) of 2,4-bis(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloric acid salt (product of PREPARATION 127) were used.

[1967] 1K NMR (CDCl3) δ 5.85-5.83 (IH, m), 5.09-4.92 (IH, m), 4.95-4.78 (IH, m),

4.23-4.08 (3H, m), 4.04-3.76 (3H, m), 3.73-3.66 (IH, m), 3.46-3.38 (IH, m), 3.36-3.21 (2H, m), 3.18-3.10 (2H, m), 2.96-2.81 (IH, m), 2.61-2.50 (IH, m), 1.43-1.41 (9H, m), 1.28-1.24 (3H, m)

[1968] Mass (m/e) 470 (M+l-Boc)

…………..

WO 2012030106

https://www.google.com/patents/WO2012030106A2?cl=en

Reaction Scheme 1

Figure PCTKR2011006260-appb-I000001

PREPARATION 1: Synthesis of diethyl 2,2-difluoropentanedioate

Figure PCTKR2011006260-appb-I000014

To a solution of ethyl bromodifluoroacetate (33.2 g) in tetrahydrofuran (94.0 g) was added ethyl acrylate (8.2 g) and copper powder (10.9 g). After heating to 50℃, TMEDA (9.5 g) was added dropwise and the reaction mixture was then stirred for 3 hours at the same temperature. Upon disappearance of ethyl acrylate as the starting material, to the reaction solution was added methyl t-butyl ether (MTBE, 73.7 g) followed by addition of 10% aqueous ammonium chloride solution (49.8 g) dropwise, and the mixture was then stirred for 30 minutes. The remaining copper residue was removed by filtration through a celite, and methyl t-butyl ether (MTBE, 66.3 g) was added to separate the layers. The separated organic layer was washed successively with 10% aqueous NH4Cl solution (66.3 g) and 3 N aqueous hydrochloric acid solution (99.6 g) in order and then distilled under reduced pressure to obtain 55.0 g of the desired title compound.

1H NMR (400 MHz, CDCl3) δ 1.26 (t, J=7.2 Hz, 3H), 1.37 (t, J=7.2 Hz, 3H), 2.37-2.49 (m, 2H), 2.55 (t, J=7.2 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 4.29 (q, J=7.2 Hz, 2H).

PREPARATION 2: Synthesis of ethyl 4,4-difluoro-5-hydroxypentanoate

Figure PCTKR2011006260-appb-I000015

14.8 g of the compound obtained from the above Preparation 1 was diluted with ethanol (20.4 g) and tetrahydrofuran (69.1 g) and then cooled to 0℃. To this solution was slowly added sodium borohydride (NaBH4, 3.5 g) stepwise while keeping the internal temperature below 30℃. After confirming completion of the reaction by 1H NMR, the reaction solution was cooled to the temperature of 10℃ and 10% aqueous ammonium chloride solution (77.7 g) was slowly added. The remaining boron compound was filtered through celite, and the filtrate was distilled under reduced pressure to remove tetrahydrofuran. Then, ethyl acetate (105.2 g) was added to separate the layers, and the organic layer was distilled under reduced pressure to obtain 10.8 g of the title compound.

1H NMR (400 MHz, CDCl3) δ 1.23 (t, J=7.2 Hz, 3H), 2.15-2.29 (m, 2H), 2.49 (t, J=7.2 Hz, 2H), 3.69 (t, J=12.0 Hz, 2H), 4.12 (q, J=4.0 Hz, 2H).

EXAMPLE 1: Synthesis of ethyl 4,4-difluoro-5-{[(trifluoromethyl)sulfonyl]oxy}- pentanoate

Figure PCTKR2011006260-appb-I000016

To the solution of 10.8 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (100.2 g) was added pyridine (7.0 g), and then the mixture was cooled to -5.0℃. After completion of cooling, trifluoromethane sulfonic acid anhydride (20.1 g) was slowly added dropwise while keeping the reaction temperature below 6.3℃. After stirring the reaction solution for 30 minutes, 1.5 N hydrochloric acid solution was added dropwise at 0℃ to separate the layers. The aqueous layer as separated was back-extracted twice with dichloromethane (33.4 g), and the extracts were combined with the organic layer separated from the above and then distilled under reduced pressure to obtain 19.7 g of the title compound as a yellow oil.

1H NMR (500 MHz, CDCl3) δ 1.27 (t, J=7.2 Hz, 3H), 2.29-2.39 (m, 2H), 2.59 (t, J=7.6 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 4.55 (t, J=11.6 Hz, 2H).

EXAMPLE 2-1: Synthesis of ethyl 4,4-difluoro-5-{[(nonafluorobutyl)sulfonyl]- oxy}pentanoate

Figure PCTKR2011006260-appb-I000017

To the solution of 100.0 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (300.0 ml) was added pyridine (65.7 g), and the mixture was then cooled to -10.0℃. After completion of cooling, nonafluorobutanesulfonic anhydride (477.4 g) was slowly added dropwise. After stirring the reaction solution for 3 hours, 1.0 N hydrochloric acid solution (300.0 ml) was added dropwise to separate the layers. The aqueous layer as separated was back extracted once with dichloromethane (500.0 ml), and the extracts were combined with the organic layer separated from the above and then distilled under reduced pressure to obtain 177.5 g of the title compound.

1H NMR (500 MHz, CDCl3) δ 1.26 (t, 3H, J=7.3 Hz), 2.30-2.36 (m, 2H), 2.58 (t, 2H, J=7.4 Hz), 4.16 (q, 2H, J=7.3 Hz), 4.57 (t, 2H, J=11 Hz).

EXAMPLE 2-2: Synthesis of ethyl 4,4-difluoro-5-{[(nonafluorobutyl)sulfonyl]- oxy}pentanoate

To the solution of 500.0 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (1000.0 ml) was added triethylamine (389.0 g), and the mixture was then cooled to 0℃. After completion of cooling, perfluorobutanesulfonyl chloride (948.80 g) was slowly added dropwise. The reaction solution was stirred for 3 hours at room temperature, distilled under reduced pressure, dissolved in methyl t-butyl ether (MTBE, 3000.0 ml) and then washed three times with water. The organic layer thus obtained was dehydrated with magnesium sulfate, filtered through a celite and then distilled under reduced pressure to obtain 960.0 g of the title compound.

EXAMPLE 3: Synthesis of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-oxo- pentanoate

Figure PCTKR2011006260-appb-I000018

To 25.0 g of the starting material, (3S)-3-[(t-butoxycarbonyl)amino]-4-oxo- pentanoic acid, was added t-butanol (96.9 g) followed by the addition of Boc2O (25.4 g) and dimethylaminopyridine (DMAP, 62.0 g, 0.5 mol%) at room temperature, and the reaction mixture was then stirred for 23 hours at 40℃. Upon completion of the reaction, ethylene dichloride (62.3 g) in t-butanol was added, and the mixture was then distilled under reduced pressure to obtain 30.7 g of the title compound.

1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 1.47 (s, 9H), 2.71 (dd, J=4.8, 16.4 Hz, 1H), 2.88 (dd, J=4.4, 16.4 Hz, 1H), 3.75 (s, 3H), 4.53 (m, 1H), 5.44 (br d, J=8.0 Hz, 1H).

EXAMPLE 4: Synthesis of tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy- butanoate

Figure PCTKR2011006260-appb-I000019

30.7 g of the compound obtained from the above Example 3 was dissolved in ethanol (112.3 g) and, after lowering the internal temperature to 10.5℃ sodium borohydride (NaBH4, 5.7 g) was slowly added dropwise. This reaction solution was stirred while maintaining the temperature below 22℃. After confirming completion of the reaction by 1H NMR and TLC, to the reaction solution was slowly added 3.0 N hydrochloric acid solution (30.7 g) dropwise at the internal temperature of 10℃ followed by addition of diluted 0.2% hydrochloric acid solution (100.0 g). The reaction solution was adjusted to pH 3~4 with addition of 9.0% aqueous hydrochloric acid solution, and then back-extracted twice with ethyl acetate (100.0 g) and toluene (44.0 g). The organic layer thus obtained was distilled under reduced pressure to obtain 25.1 g of the title compound.

1H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 1.45 (s, 9H), 2.48-2.57 (m, 2H), 3.69 (d, J=4.9 Hz, 1H), 3.97 (m, 1H), 5.22 (bs, 1H).

EXAMPLE 5: tert-butyl (3S)-[(tert-butoxycarbonyl)amino]-4-[(methylsulfonyl)oxy]- butanoate

Figure PCTKR2011006260-appb-I000020

To 25.1 g of the compound obtained from the above Example 4 was added dichloromethane (133.0 g) and triethylamine (148.0 g), and the mixture was then cooled to 0℃. To this reaction solution was slowly added methanesulfonyl chloride (11.8 g) diluted with dichloromethane (39.9 g) dropwise for 50 minutes while maintaining the internal temperature below 12℃. After completion of the reaction, the reaction solution was washed with 0.5 N aqueous hydrochloric acid solution (120.0 g) and water (100.4 g), and then distilled under reduced pressure to obtain 31.5 g of the title compound.

1H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 1.46 (s, 9H), 2.62 (d, J=6.0 Hz, 2H), 3.04 (s, 3H), 4.21 (m, 1H), 4.30 (d, J=5.2 Hz, 2H), 5.16 (br d, J=7.2 Hz, 1H).

EXAMPLE 6: Synthesis of tert-butyl (3S)-4-azido-3-[(tert-butoxycarbonyl)amino]- butanoate

Figure PCTKR2011006260-appb-I000021

Sodium azide (NaN3, 11.6 g) was diluted with dimethylacetamide (DMAc, 260.0 g). After elevating the internal temperature to 80℃, a solution of 31.5 g of the compound, as obtained from the above Example 5, diluted with dimethylacetamide (DMAc, 45.0 g) was added thereto. The reaction proceeded at 80℃ for 2 hours. To the reaction solution were added toluene (251.0 g) and water (320.0 g) to separate the layers. The organic layer thus obtained was distilled under reduced pressure to obtain 24.0 g of the title compound.

1H NMR (500 MHz, CDCl3) δ 1.47 (s, 9H), 1.49 (s, 9H), 2.49 (d, J=6.0 Hz, 2H), 3.44-3.55 (m, 2H), 4.09 (br s, 1H), 5.14 (br s, 1H).

EXAMPLE 7: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- butanoate

Figure PCTKR2011006260-appb-I000022

To 21.0 g of the compound obtained from the above Example 6 was added tetrahydrofuran (93.3 g) followed by the addition of triphenylphosphine (PPh3, 21.0 g) at 40℃, the mixture was stirred for 2 hours at the same temperature, and water (3.8 g) was then added thereto. The reaction solution was distilled under reduced pressure, and the resulting triphenylphosphine oxide solid was diluted with toluene (26.0 g) and n-hexane (41.0 g), and then filtered off. The filtrate was adjusted to pH 2~3 with 1.0 N aqueous hydrochloric acid solution (110.0 g) and then subjected to separation of the layers. To remove any residual triphenylphosphine oxide solid, the aqueous layer obtained above was washed with dichloromethane (100.0 g) and then adjusted to pH 8~9 with 28% aqueous ammonia solution (7.6 g). The aqueous solution thus obtained was extracted with dichloromethane (100.0 g) and distilled under reduced pressure to obtain 8.5 g of the title compound as a white solid.

1H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 1.45 (s, 9H), 2.45 (d, J=6.1 Hz, 2H), 2.77 (d, J=5.5 Hz, 2H), 3.87 (br s, 1H), 5.22 (br s, 1H).

EXAMPLE 8: Synthesis of N,N-dibenzyl-L-N(Boc)-aspartamide 4-tert-butyl ester

Figure PCTKR2011006260-appb-I000023

N-Boc-L-aspartic acid 4-t-butyl ester (29.0 g, 0.10 mol) was added to THF (200 ml). After cooling to temperature below -5℃, to the reaction solution was added isobutylchloroformate (13.0 ml, 0.10 mol) followed by addition of N-methyl morpholine (12.0 ml, 0.10 mol) dropwise, and the reaction mixture was stirred for over 30 minutes. To the reaction mixture was added dropwise dibenzylamine (21.1 ml, 0.11 mol), and the mixture was then stirred for over 3 hours and monitored for the reaction progress by TLC (EtOAc: Hexane=1:4). Upon completion of the reaction, the reaction solution was stirred with addition of ethyl acetate (300.0 mL) and 1 N hydrochloric acid to separate the layers, and distilled under reduced pressure to precipitate a solid. The solid was filtered and washed with ethyl acetate (100 ml), and then the washings were concentrated by distillation again under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (41.7 g, 0.89 mol).

1H NMR (400 MHz, CDCl3) δ: 7.32 (m, 5H), 7.20 (m, 5H), 5.39 (d, J=7.2 Hz, 1H), 5.30 (m, 1H), 4.87-4.77 (m, 2H), 4.48-4.39 (m, 2H), 2.72 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 2.56 (dd, J=15.8 Hz, J=6.4 Hz, 1H), 1.43 (s, 9H), 1.37 (s, 9H).

Mass (ESI, m/z): 491 (M+Na), 469 (M+H), 413 (M-55).

EXAMPLE 9: Synthesis of N, N-diallyl-L-N(Boc)-aspartamide 4-tert-butyl ester

Figure PCTKR2011006260-appb-I000024

L-N(Boc)-aspartic acid 4-t-butyl ester (5.00 g, 17.3 mol) was added to THF (50 ml). After cooling to temperature below -5℃, to the reaction solution was added isobutylchloroformate (2.26 ml, 17.3 mol) followed by addition of N-methyl morpholine (1.90 ml, 17.3 mol) dropwise, and the reaction mixture was stirred for over 30 minutes. To the reaction mixture was added dropwise diallylamine (2.35 ml, 19.0 mol), and the mixture was then stirred for over 3 hours and monitored for the reaction progress by TLC (EtOAc: Hexane=1:4). Upon completion of the reaction, the reaction solution was stirred with addition of ethyl acetate (60 ml) and 1 N hydrochloric acid and, after separating the layers, concentrated by distillation under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (6.0 g, 16.3 mol).

1H NMR (400 MHz, CDCl3) δ: 5.78 (m, 2H), 5.30 (m, 1H), 5.23-5.11 (m, 1H), 5.30 (m, 1H), 4.93 (m, 1H), 4.11-3.84 (m, 4H), 2.68 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 2.51 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 1.44 (s, 9H), 1.42 (s, 9H).

Mass (ESI, m/z): 391 (M+Na), 369 (M+H), 313 (M-55).

EXAMPLE 10: Synthesis of N,N-dibenzyl-4-amino-3(S)-N(Boc)-aminobutanoic acid 4-tert-butyl ester

Figure PCTKR2011006260-appb-I000025

10.0 g of the compound obtained from the above Example 8, Ru3(CO)12 (136 mg, 1mol%), and diphenylsilane (19.7 ml, 106.7 mmol) were added to tetrahydrofuran (50 ml), and the reaction solution was stirred under reflux for over 40 hours. The reaction solution was extracted with ethyl acetate (200 ml) and concentrated by distillation under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (4.7 g, 10.5 mmol).

1H NMR (400 MHz, CDCl3) δ: 7.31-7.20 (m, 10H), 5.12 (bs, 1H), 3.90 (bs, 1H), 3.63 (d, J=12.0 Hz, 2H), 3.48 (d, J=12.0 Hz, 2H), 3.24 (m, 1H), 3.16 (bs, 1H), 2.42 (m, 2H), 1.81 (m, 1H), 1.59 (m, 9H), 1.46 (s, 9H), 1.06 (s, 9H).

Mass (ESI, m/z): 455 (M+H), 441 (M-13).

EXAMPLE 11: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- 4-oxobutanoate

Figure PCTKR2011006260-appb-I000026

360.0 g of the starting material, N-Boc-Asp(O-t-Bu)OH, together with Boc2O (353.0 g) and ammonium bicarbonate (NH4HCO3, 123.9 g) was added to dimethylformamide (1174.6 g), and pyridine (61.0 g) was added dropwise thereto at room temperature, and the reaction mixture was then stirred for about 3 hours. Upon completion of the reaction, water (1440 ml) and toluene (1800 ml) were added to the reaction solution and stirred for 30 minutes to separate the layers. The organic layer thus obtained was distilled under reduced pressure to remove t-butanol and toluene to obtain the title compound, which was directly used in the next reaction.

EXAMPLE 12: Synthesis of (S)-tert-butyl 3-(tert-butoxycarbonylamino)-3-cyanopropanoate

Figure PCTKR2011006260-appb-I000027

To the compound obtained from Example 11 was added dimethylformamide (1019.5 g) followed by addition of cyanuric chloride (112.0 g) dropwise for 1.5 hours at temperature below 25℃. The reaction solution was stirred for one hour at room temperature, and then 0.1 N aqueous sodium hydroxide solution (1850.0 g) and toluene (1860 ml) were added thereto to separate the layers. The organic layer thus obtained was washed once again with water (700 ml) and then distilled under reduced pressure to obtain 318.3 g of the title compound.

1H NMR (500 MHz, CDCl3) δ: 1.44 (s, 9H), 1.45 (s, 9H), 2.45 (d, J=6.1 Hz, 2H), 2.77 (d, J=5.5 Hz, 2H), 3.87 (br s, 1H), 5.22 (br s, 1H).

EXAMPLE 13: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- butanoate

Figure PCTKR2011006260-appb-I000028

To 212.1 g of the compound obtained from the above Example 12 was added acetic acid (4000 ml) followed by addition of 20 wt% Pd(OH)2 (1.1 g) at 40℃. The mixture was stirred for 8 hours while keeping the internal temperature below 45℃ and 3 atmospheric pressure of hydrogen. Upon completion of the reaction, the reaction solution was distilled under reduced pressure to remove acetic acid, diluted with toluene (640 L) and then filtered through a celite. To the filtrate was added 0.25 N aqueous hydrochloric acid solution (1060 ml) to separate the layers. The aqueous layer thus obtained was basified with aqueous ammonia solution (543.1 g) and then extracted with methyl t-butyl ether (MTBE, 1000 ml). The organic layer thus obtained was distilled under reduced pressure to obtain 185.0 g of the title compound.

EXAMPLE 14: Synthesis of 3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxo- piperidin-1-yl)-butyric acid t-butyl ester

Figure PCTKR2011006260-appb-I000029

Triethylamine (13.2 g) was added to 16.0 g of the compound obtained from the above Example 1 or 2-1 or 2-2, and 14.1 g of the compound obtained from the above Example 7 or 13, and the mixture was then stirred for 21 hours at 40℃. Then, dichloromethane (154.8 g) and acetic acid (18.3 g) were added, and the mixture was stirred for 5 hours at room temperature. To the resulting reaction solution was added 0.5 N aqueous hydrochloric acid solution (116.8 g) and then, the mixture was stirred for 30 minutes to separate the layers. The organic layer thus obtained was distilled under reduced pressure to obtain 23.6 g of the title compound.

1H NMR (500 MHz, CDCl3) δ: 1.42 (s, 9H), 1.46 (s, 9H), 2.27 (m, 2H), 2.40-2.64 (m, 4H), 3.20 (dd, J=4.3, 13.5 Hz, 1H), 3.56-3.70 (m, 2H), 3.76-3.91 (m, 2H), 4.16 (m, 1H), 5.20 (d, J=8.6 Hz, 1H).

EXAMPLE 15: Synthesis of 3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxo- piperidin-1-yl)-butyric acid

Figure PCTKR2011006260-appb-I000030

23.6 g of the compound obtained from the above Example 14 was added to dichloromethane (20.0 g) followed by addition of H3PO4 (30.0 g), and the mixture was stirred for 16 hours at room temperature. After confirming the detachment of all of t-butyl group and t-butyloxycarbonyl group, the reaction solution was adjusted to pH 7.0~8.0 with 10 N aqueous hydrogen peroxide, and Boc2O (16.0 g) was added thereto. After completion of the addition, 10 N aqueous hydrogen peroxide was used to maintain the pH of the reaction solution at 8.0~9.0. After stirring for 3 hours, the resulting sodium phosphate was filtered off, and the filtrate was then adjusted to pH 2.0~3.0 with 3.0 N aqueous hydrochloric acid solution. The resulting solid was filtered and dried under nitrogen to obtain 14.5 g of the title compound.

1H NMR (500 MHz, CDCl3) δ: 1.32 (s, 9H), 2.20-2.43 (m, 6H), 3.26-3.31 (m, 2H), 3.61 (m, 1H), 3.81 (m, 1H), 4.02 (m, 1H), 6.73 (d, J=8.6 Hz, 1H), 12.16 (s, 1H).

For the title compound resulting from the above, its enantiomeric isomers―i.e. S-form and R-form―were measured by HPLC (high-performance liquid chromatography), and an excess of the enantiomeric isomers (S vs. R form) (enantiomeric excess; ee) was then calculated as being ee > 99%. On the other hand, in case of the Comparative Example prepared according to the prior method based on WO 06/104356, as described below, the excess (ee) of enantiomeric isomers (S vs. R form) was 80%. From this, it can be identified that the compound of formula (2) having an optically high purity could be obtained according to the method of the present invention.

COMPARATIVE EXAMPLE 1: Synthesis of 3-t-butoxycarbonylamino-4-(5,5- difluoro-2-oxo-piperidin-1-yl)-butyric acid t-butyl ester

COMPARATIVE EXAMPLE 1-1: Synthesis of methyl 5-amino-4,4-difluoro- pentanoate HCl

Figure PCTKR2011006260-appb-I000031

To 10.0 g of the compound obtained from Example 1 was added 40 ml of anhydrous ammonia solution (7 M solution in methanol), and the mixture was stirred for 3 hours. The reaction solution was distilled and 30 ml of hydrochloric acid solution saturated with methanol was added dropwise thereto. The reaction mixture was stirred at room temperature and then distilled to obtain 7.2 g of the title compound as a white solid.

1H NMR (500 MHz, CD3OD) δ: 2.35 (m, 2H), 2.59 (t, J=7.6 Hz, 2H), 3.49 (t, J=15.3 Hz, 2H), 3.68 (s, 3H).

COMPARATIVE EXAMPLE 1-2: Synthesis of 3-t-butoxycarbonylamino-4-(5,5- difluoro-2-oxo-piperidin-1-yl)-butyric acid t-butyl ester

To the solution of the compound (1.93 g), as obtained from the above Example 4, dissolved in dichloromethane (20.0 g) and H2O (4.0 g) were added NaBr (0.8 g) and TEMPO (11 mg, 1 mol%). To this reaction solution was slowly added a solution of 5% NaOCl (11.5 g) and NaHCO3 (1.7 g) dissolved in H2O (12.0 g) dropwise for about 2 hours while maintaining the temperature below 5℃. Upon completion of dropwise addition, the reaction solution was stirred for 30 minutes to separate the layers. To the organic layer thus obtained was added the compound (1.6 g) obtained from the above Comparative Example 1-1. After stirring for 15 minutes at room temperature, NaBH(OAc)3 (2.23 g) was added to the reaction solution. After stirring for about 19 hours, 10% aqueous NaHCO3 solution (20.0 g) and 0.5 N aqueous hydrochloric acid solution (20.0 g) were added dropwise to the reaction solution to separate the layers. The organic layer thus obtained was dehydrated under anhydrous MgSO4 to obtain 2.0 g (yield 73%) of the same title compound as Example 14, as a yellow solid. For the title compound resulting from the above, its enantiomeric isomers―i.e., S-form and R-form―were measured by HPLC (high-performance liquid chromatography), and an excess (ee) of the enantiomeric isomers (S vs. R form) was then calculated as being ee = 80%.

WO2006104356A1 Mar 30, 2006 Oct 5, 2006 Seong Cheol Bu Dipeptidyl peptidase-iv inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
EP0279435A2 * Feb 18, 1988 Aug 24, 1988 BASF Aktiengesellschaft Process for the reduction of mono- and dicarboxylic acids
US5556982 * Jul 12, 1993 Sep 17, 1996 Neorx Corporation Metal radionuclide labeled proteins for diagnosis and therapy
US20080039517 * Aug 7, 2007 Feb 14, 2008 Washburn David G Pyrrolidinone anilines as progesterone receptor modulators

Footnotes

  1. Lim KS, Kim JR, Choi YJ, Shin KH, Kim KP, Hong JH, Cho JY, Shin HS, Yu KS, Shin SG, Kwon OH, Hwang DM, Kim JA, Jang IJ (October 2008). “Pharmacokinetics, pharmacodynamics, and tolerability of the dipeptidyl peptidase IV inhibitor LC15-0444 in healthy Korean men: a dose-block-randomized, double-blind, placebo-controlled, ascending single-dose, Phase I study”. Clin Ther 30 (10): 1817–30. doi:10.1016/j.clinthera.2008.10.013PMID 19014837.
  2.  Ábel T. “A New Therapy of Type 2 Diabetes: DPP-4 Inhibitors”. In Rigobelo EC. Hypoglycemia – Causes and Occurrences. Croatia: InTech. pp. 3–52. doi:10.5772/23604ISBN 978-953-307-657-7.
  3.  Kaji K (Mar 2014). “Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats.”J Gastroenterol.. 49 (3): 481–91.doi:10.1007/s00535-013-0783-4PMID 23475323.
  4.  Min HS (Jun 2014). “Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction.”Lab Invest. 94 (5): 598–607.doi:10.1038/labinvest.2014.50PMID 24687121.
  5.  Gouni-Berthold I (2014). “The role of oral antidiabetic agents and incretin mimetics in type 2 diabetic patients with non-alcoholic Fatty liver disease.”Curr Pharm Des. 20 (5): 3705–15.PMID 24040873.

Further reading

 Kim SE, Yi S, Shin KH, Kim TE, Kim MJ, Kim YH, Yoon SH, Cho JY, Shin SG, Jang IJ, Yu KS (January 2012). “Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase IV inhibitor LC15-0444and pioglitazone in healthy volunteers”Int J Clin Pharmacol Ther. 50 (1): 17–23. doi:10.5414/cp201568PMID 22192641.

External links

DAVID G. WASHBURN ET AL.: ‘Discovery or orally active, pyrrolidinone-based progesterone receptor partial agonist‘ BIOORGANIC & MEDICINAL CHEMISTRY LETTERS vol. 19, no. 16, 2009, pages 4664 – 4667, XP026419052
2 * MONICA LOPEZ-GARCIA ET AL.: ‘Synthesis of (R)-3,4- diaminobutanoic acid by desymmetrization of dimethyl 3-(benzylamino)-glutarate through enzymatic ammonolysis‘ JOURNAL OF ORGANIC CHEMISTRY vol. 68, no. 2, 2003, pages 648 – 651, XP055105976

 

09b37-misc2b027LIONEL MY SON

He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy


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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 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 amcrasto@gmail.com, 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......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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