Making HSQC look nicer « Naturalproductman’s Blog

Malleobactin Structure Elucidated

A team of scientists based in Germany have elucidated the structure and absolute configuration of malleobactin, which is the siderophore of the pathogenic Burkholderia mallei. Siderophores are strong iron-binding agents, and act as virulence factors for pathogenic bacteria.

The virulence factor malleobactin has been shown to contain an unprecedented nitro-bearing amino acid
Read more



http://www.chemistryviews.org/details/ezine/4997511/Malleobactin_Structure_Elucidated.html





TALE A TOUR


  Isle Of Capri, Italy.



 

 


 
 

 
 
 
 

 

 

 
 

 

 
 



 

 

 

 
 

 




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Computed NMR spectra predicts the structure of Nobilisitine A

Nobilisitine A was isolated by Evidente and coworkers, who proposed the structure 1.¹ Banwell and co-workers then synthesized the enantiomer of 1, but its NMR did not correspond to that of reported for Nobilisitine A.; the largest differences are 4.7 ppm for the ¹³C NMR and 0.79 ppm for the ¹H NMR.²

1

Lodewyk and Tantillo³ examined seven diastereomers of 1, all of which have a cis fusion between the saturated 5 and six-member rings (rings C and D). Low energy conformations were computed for each of these diasteromers at B3LYP/6-31+G(d,p). NMR shielding constants were then computed in solvent (using a continuum approach) at mPW1PW91/6-311+G(2d,p). A Boltzmann weighting of the shielding contants was then computed, and these shifts were then scaled as described by Jain, Bally and Rablen⁴ (discussed in this post). The computed NMR shifts for 1 were compared with the experimental values, and the mean deviations for the ¹³C and ¹H svalues is 1.2 and 0.13 ppm, respectively. (The largest outlier is 3.4 ppm for ¹³C and 0.31 for ¹H shifts.) Comparison was then made between the computed shifts of the seven diasteomers and the reported spectrum of Nobilisitine A, and the lowest mean deviations (1.4 ppm for ¹³C and 0.21 ppm for ¹H) is for structure 2. However, the agreement is not substantially better than for a couple of the other diasteomers.

2

They next employed the DP4 analysis developed by Smith and Goodman⁵ for just such a situation – where you have an experimental spectrum and a number of potential diastereomeric structures. (See this post for a discussion of the DP4 method.)The DP4 analysis suggests that 2 is the correct structure with a probability of 99.8%.

Banwell has now synthesized the compound with structure 2 and its NMR matches that of the original natural product.⁶ Thus Nobilisitine A has the structure 2.

References

(1) Evidente, A.; Abou-Donia, A. H.; Darwish, F. A.; Amer, M. E.; Kassem, F. F.; Hammoda, H. A. m.; Motta, A., "Nobilisitine A and B, two masanane-type alkaloids from Clivia nobilis,"Phytochemistry, 1999, 51, 1151-1155, DOI: 10.1016/S0031-9422(98)00714-6.

(2) Schwartz, B. D.; Jones, M. T.; Banwell, M. G.; Cade, I. A., "Synthesis of the Enantiomer of the Structure Assigned to the Natural Product Nobilisitine A," Org. Lett., 2010, 12, 5210-5213, DOI:10.1021/ol102249q

(3) Lodewyk, M. W.; Tantillo, D. J., "Prediction of the Structure of Nobilisitine A Using Computed NMR Chemical Shifts," J. Nat. Prod., 2011, 74, 1339-1343, DOI: 10.1021/np2000446

(4) Jain, R.; Bally, T.; Rablen, P. R., "Calculating Accurate Proton Chemical Shifts of Organic Molecules with Density Functional Methods and Modest Basis Sets," J. Org. Chem., 2009, DOI:10.1021/jo900482q.

(5) Smith, S. G.; Goodman, J. M., "Assigning Stereochemistry to Single Diastereoisomers by GIAO NMR Calculation: The DP4 Probability," J. Am. Chem. Soc., 2010, 132, 12946-12959, DOI:10.1021/ja105035r

(6) Schwartz, B. D.; White, L. V.; Banwell, M. G.; Willis, A. C., "Structure of the Lycorinine Alkaloid Nobilisitine A," J. Org. Chem., 2011, ASAP, DOI: 10.1021/jo2016899

Absolute Configuration of (+)-Erythro-Mefloquine

 

The absolute configuration of (+)-erythro-mefloquine has been confirmed by X-ray crystallography, CD spectroscopy, and molecular modeling
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http://www.chemistryviews.org/details/ezine/4948391/Absolute_Configuration_of_-Erythro-Mefloquine.html

Absolute Configuration and Antimalarial Activity of erythro-Mefloquine Enantiomers,
Alexandra Dassonville-Klimpt, Christine Cézard, Catherine Mullié, Patrice Agnamey, Alexia Jonet, Sophie Da Nascimento, Mathieu Marchivie, Jean Guillon, Pascal Sonnet,
ChemPlusChem 2013.
DOI: 10.1002/cplu.201300074

The Absolute Configuration of (+)- and (−)-erythro-Mefloquine,
Michael Müller, Claudia M. Orben, Nina Schützenmeister, Manuel Schmidt, Andrei Leonov, Uwe M. Reinscheid, Birger Dittrich, Christian Griesinger,
Angew. Chem. Int. Ed. 2013.
DOI: 10.1002/anie.201300258

1-Adamantyl cation – Predicting its NMR spectra

1-Adamantyl cation – Predicting its NMR spectra

What is required in order to compute very accurate NMR chemical shifts? Harding, Gauss and Schleyer take on the interesting spectrum of 1-adamantyl cation to try to discern the important factors in computing its ¹³C and ¹H chemical shifts.¹

1

To start, the chemical shifts of 1-adamtyl cation were computed at B3LYP/def2-QZVPP and
MP2/qz2p//MP2/cc-pVTZ. The root means square error (compared to experiment) for the carbon chemical shifts is large: 12.76 for B3LYP and 6.69 for MP2. The proton shifts are predicted much more accurately with an RMS error of 0.27 and 0.19 ppm, respectively.

The authors speculate that the underlying cause of the poor prediction is the geometry of the molecule. The structure of 1 was optimized at HF/cc-pVTZ, MP2/cc-pVTZ and CCSD(T)/pVTZ and then the chemical shifts were computed using MP2/tzp with each optimized geometry. The RMS error of the ¹²C chemical shifts are HF/cc-pVTZ: 9.55, MP2/cc-pVTZ: 5.62, and CCSD(T)/pVTZ: 5.06. Similar relationship is seen in the proton chemical shifts. Thus, a better geometry does seem to matter. The CCSD(T)/pVTZ optimized structure of 1 is shown in Figure 1.

1

Figure 1. CCSD(T)/pVTZ optimized structure of 1.

Unfortunately, the computed chemical shifts at CCSD(T)/qz2p//CCSD(T)/cc-pVTZ are still in error; the RMS is 4.78ppm for the carbon shifts and 0.26ppm for the proton shifts. Including a correction for the zero-point vibrational effects and adjusting to a temperature of 193 K to match the experiment does reduce the error; now the RMS for the carbon shifts is 3.85 ppm, with the maximum error of 6 ppm for C3. The RMS for the proton chemical shifts is 0.21ppm.

The remaining error they attribute to basis set incompleteness in the NMR computation, a low level treatment of the zero-point vibrational effects (which were computed at HF/tz2p), neglect of the solvent, and use of a reference in the experiment that was not dissolved in the same media as the adamantyl cation.

So, to answer our opening question – it appears that a very good geometry and treatment of vibrational effects is critical to accurate NMR shift computation of this intriguing molecule. Let the
computational chemist beware!

References

(1) Harding, M. E.; Gauss, J.; Schleyer, P. v. R., "Why Benchmark-Quality Computations Are Needed To Reproduce 1-Adamantyl Cation NMR Chemical Shifts Accurately," J. Phys. Chem. A, 2011, 115, 2340-2344, DOI: 10.1021/jp1103356

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Welwitindolinones structure

A quick note here on the use of computed NMR to determine stereochemical structure. The Garg group synthesized two “oxidized welwitindolines”, compounds 1 and 2.¹ The relative stereochemistry at the C3 position (the carbon with the hydroxy group) was unknown.

1

2

Low energy gas-phase conformers of both epimers of 1 and 2 were optimized at B3LYP/6-31+G(d,p). (These computations were done by the Tantillo group.) See Figure 1 for the optimized lowest energy conformers. Using these geometries the NMR chemical shifts were computed at mPW1PW91/6-311+G(d,p) with implicit solvent (chloroform). The chemical shifts were Boltzmann-weighted and scaled according to the prescription (see this post) of Jain, Bally and Rablen.² The computed chemical shifts were then compared against the experimental NMR spectra. For both 1and 2, the ¹³C NMR shifts could not readily distinguish the two epimers. However, the computed ¹H chemical shifts for the S epimer of each compound was significantly in better agreement with the experimental values; the mean average deviation for the S epimer of 2 is 0.08 ppm but 0.36ppm for the R epimer. As a check of these results, DP4 analysis³ (see this post) of 2 indicated a 100% probability for the S epimer using only the proton chemical shifts or with the combination of proton and carbon data.

1

2

Figure 1. B3LYP/6-31+G(d,p) optimized geometries of the
lowest energy conformations of 1 and 2.

References

(1) Quasdorf, K. W.; Huters, A. D.; Lodewyk, M. W.; Tantillo, D. J.; Garg, N. K., "Total Synthesis of Oxidized Welwitindolinones and (-)-N-Methylwelwitindolinone C Isonitrile," J. Am. Chem. Soc. 2011,134, 1396-1399, DOI: 10.1021/ja210837b

(2) Jain, R.; Bally, T.; Rablen, P. R., "Calculating Accurate Proton Chemical Shifts of Organic Molecules with Density Functional Methods and Modest Basis Sets," J. Org. Chem. 2009, 74, 4017-4023, DOI: 10.1021/jo900482q.

(3) Smith, S. G.; Goodman, J. M., "Assigning Stereochemistry to Single Diastereoisomers by GIAO NMR Calculation: The DP4 Probability," J. Am. Chem. Soc. 2010, 132, 12946-12959, DOI:10.1021/ja105035r

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Omarigliptin

OMARIGLIPTIN. MK 3102

1226781-44-7

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)oxan-3-amine

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine

1226781-44-7, Omarigliptin [USAN], UNII-CVP59Q4JE1, CHEMBL2105762, MK-3102, PB39113

Molecular Formula: C₁₇H₂₀F₂N₄O₃S   Molecular Weight: 398.427506

IN PHASE 3

CLICK ON IMAGES FOR CLARITY VIEW

PAPER

J. Med. Chem., 2014, 57 (8), pp 3205–3212

DOI: 10.1021/jm401992e

http://pubs.acs.org/doi/abs/10.1021/jm401992e

In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.

Omarigliptin (MK-3102) (2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine,is a 2,3,5-substituted tetrahydropyran analogue currently in phase 3 clinical trial for type 2 diabetes mellitus (T2DM).

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine, Omarigliptin

Crystallization from ethyl acetate gave a compound with greater than 99% purity.

Optical rotation [α]_D²⁰ −12.0° (c 1.0, CH₃OH).

¹H NMR (CD₃OD, 500 MHz) δ = 1.71 (q, 1H, J = 12 Hz), 2.56–2.61 (m, 1H), 3.11–3.18 (m, 1H), 3.36–3.40 (m, 1H), 3.48 (t, 1H, J = 12 Hz), 3.88–3.94 (m, 4H), 4.30–4.35 (m, 1H), 4.53 (d, 1H, J = 12 Hz), 7.14–7.23 (m, 2H), 7.26–7.30 (m, 1H), 7.88 (s, 1H).

LC–MS: 399.04 (M + 1).

PATENT

http://www.google.com.tr/patents/US20100120863?hl=tr&cl=ja

Example 1

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amineStep A: tert-Butyl {(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5 (4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate

A mixture of Intermediate 2 (26.3 g, 80 mmol) and 2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (Intermediate 5) (15.07 g, 80 mmol) in anhydrous methanol (1.5 L) was stirred at room temperature for 2 h. To the resulting white suspension was added decaborane (2.95 g, 24.15 mmol) and the mixture was stirred at room temperature overnight. Methanol was removed and the residue was purified on two 65i Biotage™ columns eluting with 5-50% ethyl acetate in dichloromethane to afford the title compound as a white solid. LC-MS: 499.10 (M+1).

Step B: (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine

Removal of the BOC group in the product from Step A (13.78 g, 27.67 mmol) was accomplished with trifluoroacetic acid (100 ml) in dichloromethane (200 mL) at room temperature. After stirring for 2 h, the reaction was concentrated and neutralized with 25% MeOH and 2.5% ammonium hydroxide in dichloromethane. Solvents were removed under reduced pressure and the resulting crude material was purified on a 65i Biotage™ column eluting with 1.25-5% MeOH and 0.125-0.5% ammonium hydroxide in dichloromethane. The isolated material was further purified by recrystallization from 5:1 EtOAc/CH₂Cl₂ at 60° C. The crystalline product was washed with cold 2:1EtOAc/hexanes to give the title compound as a light brown solid. ¹H NMR (500 MHz, CD₃OD): 1.71 (q, 1H, J=12 Hz), 2.56-2.61 (m, 1H), 3.11-3.18 (m, 1H), 3.36-3.40 (m, 1H), 3.48 (t, 1H, J=12 Hz), 3.88-3.94 (m, 4H), 4.30-4.35 (m, 1H), 4.53 (d, 1H, J=12 Hz), 7.14-7.23 (m, 2H), 7.26-7.30 (m, 1H), 7.88 (s, 1H). LC-MS: 399.04 (M+1).

Intermediate 2

tert-Butyl[(2R,3S)-5-oxo-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate Step A: 1-(2,5-Difluorophenyl)-2-nitroethanol

To sodium hydroxide (1N, 3L) and methanol (1500 mL) at 5° C. was added a solution of 2,5-difluorobenzaldehyde (350 g, 2.46 mol) and nitromethane (157 mL, 2.9 mol) in methanol (350 mL) dropwise over a period of 1 h. The reaction mixture was then neutralized with glacial acetic acid (165 mL). Diethyl ether (1500 mL) was added and the layers separated. The organic layer was washed successively with saturated aqueous sodium carbonate solution (1000 mL), and saturated aqueous brine (1000 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to afford 1-(2,5-difluorophenyl)-2-nitroethanol that was used without further purification in Step B.

Step B: 2-Nitro-1-(2,5-difluorophenyl)ethanone

A solution of Dess-Martin periodinane (125 g) in dichloromethane (600 mL) was added to a solution of the nitroalcohol made in Step A (46.3 g) at 10° C. over a period of 30 min. Stirring was continued for 2 h, and the reaction mixture was then poured onto a mixture of sodium bicarbonate (300 g) and sodium thiosulfate (333 g) in water (3 L). The desired product was extracted with methyl t-butyl ether (MTBE) (2 L). The aqueous layer was neutralized with HCl (2N, 1.5 L) and extracted with MTBE (3 L). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, evaporated and the residue was purified by chromatography (silica gel, eluting with dichloromethane) to yield the desired nitroketone.

Step C: 3-Iodo-2-(iodomethyl)prop-1-ene

A mixture of 3-chloro-2-(chloromethyl)prop-1-ene (1.0 g, 8 mmol) and sodium iodide (6.6 g, 44 mmol) in acetone (60 mL) was stirred at room temperature for 20 h, evaporated under reduced pressure and partitioned between dichloromethane (150 mL) and water (50 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to yield 3-iodo-2-(iodomethyl)prop-1-ene as a reddish oil.

Step D: 3-Methylene-5-nitro-6-(2,5-difluorophenyl)-3,4-dihydro-2H-pyran

N,N-diisopropylethylamine (184 mL) was added to a solution of 2-nitro-1-(2,5-difluorophenyl)ethanone (92.7 g, 461 mmol) in N,N-dimethylformamide (1000 mL) and 3-iodo-2-(iodomethyl)prop-1-ene (156 g, 507 mmol). The mixture was heated at 60° C. for 2 h, evaporated and purified by chromatography (silica gel, gradient 0-30% dichloromethane in hexane) to yield 3-methylene-5-nitro-6-(2,5-difluorophenyl)-3,4-dihydro-2H-pyran.

Step E: (2R,3S)-5-Methylene-3-nitro-2-(2,5-difluorophenyl)tetrahydro-2H-pyran

This compound was made by following the same method described in Intermediate 1, Step D by using 3-methylene-5-nitro-6-(2,5-trifluorophenyl)-3,4-dihydro-2H-pyran.

Step F: (2R,3S)-5-Methylene-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

This compound was made by following the same method described in Intermediate 1, Step E by using (2R,3S)-5-Methylene-3-nitro-2-(2,5-difluorophenyl)tetrahydro-2H-pyran.

Step G: tert-Butyl[(2R,3S)-5-methylene-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate

This compound was made by following the same method described in Intermediate 1, Step F by using (2R,35)-5-methylene-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine.

Step H: tert-Butyl[(2R,3S)-5-hydroxy-5-(hydroxymethyl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate

This compound was made by following the same method described in Intermediate 1, Step G by using tert-butyl[(2R,35)-5-methylene-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate.

Step I: tert-Butyl[(2R,3S)-5-oxo-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate

To a solution of tert-butyl[(2R,3S)-5-hydroxy-5-(hydroxymethyl)-2-(2,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate (10.5 g) in methanol (100 mL) at 0° C. was added pyridine (7.8 mL) and lead tetraacetate (21.7 g). The reaction mixture was stirred for 20 min. Aqueous work-up with ethyl acetate gave crude product which was purified by chromatography (silica, 0-50% ethyl acetate/heptane) to yield tert-butyl[(2R,35)-5-oxo-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate as white solid.

Intermediate 3

Step A: tert-Butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate

A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (40 g, 216 mmol) was treated with DMF-DMA (267 g, 2241 mmol) and heated at 105° C. for 40 min. The solution was cooled and evaporated under reduced pressure and the resulting orange solid was treated with hexane (200 mL) and cooled in a refrigerator for 3 days. The resulting brownish-yellow solid obtained as such was collected by filtration, dried and used in the next step without further purification.

Step B: 1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazole

A solution of hydrazine (3 mL) and tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (19.22 g) in ethanol (40 mL) was heated at 85° C. in a sealed tube for 4 h. Solvent was removed under reduced pressure, and the residue was triturated with dichloromethane (160 mL) and ethyl acetate (15 mL). The resulting solid was filtered. The filtrate was concentrated and the resulting solid was triturated again and filtered. The combined solids were treated with 4N hydrochloric acid (250 mL) in methanol and stirred for 6 h. The reaction mixture was concentrated and dried. The resulting solid was treated again for 6 h with 4N hydrochloric acid (250 mL) in methanol. After concentration and drying, the resulting hydrochloride salt was treated with ammonia in methanol (2N, 300 mL) and ammonium hydroxide solution in water (28%, 30 mL) and concentrated to dryness. The solid obtained was treated with methanol (70 mL) and water (5 mL) and purified in three batches on Biotage Horizon® system (silica, gradient 5-17% methanol containing 10% concentrated ammonium hydroxide in ethyl acetate) to yield 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole. ¹H NMR (500 MHz, CD₃OD): δ 4.04 (d, 4H); 7.39 (s, 1H).

Intermediate 5

2-(Methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole Step A: tert-Butyl 1-(methylsulfonyl)]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (A) and tent-butyl 2-(methylsulfonyl)]-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (B)

A suspension of N-Boc-pyrazolopyrrolidine (Intermediate 3, Step B) (27.16 g, 130 mmol) in anhydrous acetonitrile (1.0 L) was charged in a 2.0 L three-neck flask fitted with a thermometer and an addition funnel and then treated with sodium hydride (60% dispersion in oil, 6.23 g, 156 mmol) while under nitrogen atmosphere in one portion. The reaction mixture was stirred at room temperature for 2 h. The resulting white suspension was then cooled in an ice bath and methanesulfonyl chloride (25.2 mL, 324 mmol) was slowly added via addition funnel The ice bath was then removed and the mixture was stirred 1 h at room temperature. The reaction mixture was quenched with water (500 mL) and the layers were separated. The aqueous layer was then extracted with 2×500 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a mixture of products A and B as colorless syrups. NMR in CD₃OD indicated a 1:1 mixture of two products, in which the proton on the pyrazole ring in product A appeared at 7.70 ppm while the proton in product B appeared at 7.95 pm. LC-MS: 288.08 (M+1).

Step B: 2-(Methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

Trifluoroacetic acid (200 mL) was added slowly to a solution containing intermediates A and B prepared in the previous step (48.4 g, 168 mmol) in dichloromethane (400 mL) at 0° C. After addition, the cooling bath was removed and the reaction was allowed to stir at room temperature for 2 h. Solvent was removed under reduced pressure and the resulting trifluoroacetate salt was then neutralized with 500 mL of 25% methanol and 2.5% ammonium hydroxide in dichloromethane. After removal of solvent, the desired Intermediate 5 was obtained after chromatography on a Biotage™ column (2×340 g) eluting with 2.5-12.5% methanol and 0.25-1.25% ammonium hydroxide in dichloromethane. LC-MS: 109.85 (M+1).

PATENT

below   patent  caution................similar not same....examples below will help you in synthesis similarities

http://www.google.com/patents/WO2014018355A1?cl=en

Step 1 ² Step 2

Example 1

Synthesis of 3: (Step 1 & 2)

Dimethyldisulfide 1 (5 g, 53 mmol) and acetic acid (6 mL, 106 mmol) were mixed under nitrogen atmosphere and cooled to - 20 °C. Sulfuryl chloride (13 mL, 159 mmol) was added dropwise with stirring. The mixture was then stirred for 1 hour at -20 °C and afterwards allowed to come to room temperature and continued for another two hours. Acetyl chloride was distilled off from the reaction mixture. Crude methanesulfinyl chloride 2 obtained was used in the next step without further purification.

To a solution of chloramine T (14.95 g, 53 mmol) in dry toluene (220 mL) was added a solution of methanesulfinyl chloride 2 (5.2 g, 53 mmol) in dry toluene (10 mL) at 0 °C. The resulting suspension was heated at 80 °C for 2 hours with stirring. After cooling, the solid was filtered off and washed with dry toluene (100 mL). The filtrate was evaporated in vacuo and the crude mixture was purified through silica gel chromatography to obtain 3 as off white solid. ^XH NMR (300 MHz, CDC1₃): δ 7.85 - 7.91 (m, J= 8.42 Hz, 2H), 7.31 - 7.38 (m, J= 8.23 Hz, 2H), 3.78 (s, 3H), 2.45 (s, 3H).

Synthesis of 4: (Step 3)

To a solution of Ml (1.0 g, 2.2 mmol) in THF (10 mL) and DMF (10 mL) under nitrogen atmosphere at 0 °C was added Et₃N (0.92 mL, 6.6 mmol) followed by B0C₂O (0.48 g, 2.2 mmol). The reaction mixture was allowed to come to room temperature and continued the stirring for over night. The reaction mixture was diluted with water (100 mL) and extracted with CH₂CI₂ (3 x 100 mL). Combined organics were dried over Na₂S0₄, filtered, concentrated under vacuum and purified by silica gel chromatography afforded 4 as a off white solid.

^XH NMR (400 MHz, CDC1₃): δ 7.27 - 7.35 (m, 1H), 4.44 - 4.54 (m, 4H), 1.52 (s, 9H).

Synthesis of 5: (Step 4)

To a suspension of NaH (0.30 g, 7.5 mmol) in dry THF (5 mL) under nitrogen atmosphere at 0 °C was added a solution of 4 (0.78 g, 3.7 mmol) in dry THF (30 mL). The reaction mixture was allowed to come to room temperature and continued the stirring for 2 hours. Reaction mixture was again cooled to 0 °C. A solution of 3 (2.0 g, 7.4 mmol) in THF (25 mL) was added to the reaction mixture and continued the stirring for another 1 hour. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 200 mL). Combined organics were dried over Na₂S0₄, filtered, concentrated under vacuum and purified by silica gel chromatography afforded 5 as an off-white solid.

^XH NMR (400 MHz, CDC1₃): δ 7.84 - 7.88 (m, 1H), 7.78 (t, J= 8.27 Hz, 2H), 7.23 - 7.30 (m, 2H), 4.39 - 4.49 (m, 4H), 3.53 (d, J= 2.40 Hz, 3H), 2.42 (s, 3H), 1.53 (s, 9H).; Molecular Formula: Ci₈H24N₄0₅S₂; LCMS purity: 98.18%; Expected: 440.1 ; Observed: 341.0 (M-99).

Synthesis of 6: (Step 5)

To a solution of 5 (0.47 g, 1.06 mmol) in dry CH₂CI₂ (1 1 mL) under nitrogen atmosphere at 0 °C was added TFA (3 mL). The reaction mixture was allowed to come to room temperature and continued the stirring for 2 hours. Solvent was removed under vacuum and solid mass was washed with Et₂0 (3 x 10 mL) to get amine TFA salt as white solid.

^XH NMR (300 MHz, CD₃OD): δ 7.78 (s, 1H), 7.63 - 7.70 (m, J= 8.11 Hz, 2H), 7.26 - 7.35 (m, J = 8.33 Hz, 2H), 3.93 (s, 2H), 3.86 (s, 2H), 3.34 (s, 3H), 2.42 (s, 3H).

The amine TFA salt was dissolved in minimum volume of MeOH:CHCi₃ (1 : 1) and passed through a column [Orochem 5 g, 10 ml, Amino (N¾)] using MeOH as eluent.

Organics were concentrated under vacuum to get free 6.

Synthesis of 7: (Step 6) To a stirred solution of 6 (0.34 g, 0.95 mmol) and M2 (0.26 g, 0.79 mmol) in DMAc (6.78 mL) under nitrogen atmosphere for 10 minutes was added AcOH (0.067 mL, 1.19 mmol). The reaction mixture was stirred for further 5 minutes and cooled to 0 °C. NaBH(OAc)3 (0.20 g, 0.95 mmol) was added to the reaction mixture and allowed to stirrer at room temperature for overnight. NH₄OH (2 mL) was added to the reaction mixture and heated at 50 °C for 1 hour followed by water (3.39 mL) and again heated at 50 °C for another hour. Reaction mixture was cooled to room temperature and filtered. The solid residue was washed with water (4 x 100 mL) and the crude residue was purified by silica gel chromatography to afford 7.

XH NMR (300 MHz, CDC1₃): δ 7.80 (d, J= 6.95 Hz, 3H), 7.25 - 7.29 (m, 2H), 7.22 (br. s., 1H), 6.92 - 7.02 (m, 2H), 4.52 (d, J= 9.33 Hz, 1H), 4.24 - 4.40 (m, 2H), 3.85 (br. s., 5H), 3.48 (s, 3H), 3.39 - 3.47 (m, 1H), 3.07 (br. s., 1H), 2.52 (d, J= 10.25 Hz, 1H), 2.44 (s, 3H), 1.61 (br. s., 1H), 1.28 (s, 9H).; Molecular Formula: C₂9H35F₂N₅0₆S₂; LCMS purity: 99.08%; Expected: 651.2; Observed: 652.0 (M+l). Synthesis of Example 1: (Step 7)

To a solution of 7 (20 mg, 0.03 mmol) in dry CH2CI2 (2 mL) under nitrogen atmosphere at 0 °C was added TFA (0.5 mL). The reaction mixture was allowed to come to room temperature and continued the stirring for 2 hours. Solvent was removed under vacuum and solid mass was washed with Et₂0 to get amine di-TFA salt Example 1 as white solid. Unless otherwise noted the IC50 values were determined using the assay discussed earlier.

^XH NMR (400 MHz, CD₃OD): δ 8.05 (s, 1H), 7.73 (d, J= 8.03 Hz, 2H), 7.36 (d, J= 8.28 Hz, 2H), 7.29 - 7.34 (m, 1H), 7.20 - 7.27 (m, 2H), 4.71 (d, J= 10.04 Hz, 1H), 4.40 - 4.53 (m, 5H), 3.72 - 3.82 (m, 2H), 3.68 (s, 3H), 3.59 - 3.65 (m, 1H), 2.77 - 2.85 (m, 1H), 2.44 (s, 3H), 2.00 - 2.14 (m, 1H).; Molecular Formula: C₂4H₂7F_{2 5}0₄S₂; HPLC purity: 99.74%; LCMS Expected: 551.2; Observed: 552.2 (M+l).

SCHEME 2

Example 2: Synthesis of Compound 1 & 2 (Step 1):

To a suspension of M2 (0.95 g, 2.8 mmol) in water (8.67 mL) was added sodium metabisulfite (0.55 g, 2.8 mmol) and stirred a room temperature for lhour. A solution of M3* (0.52 g, 2.8 mmol) in ethanol (8.67 mL) was added to the above reaction mixture and continued the stirring for further 4 hours. Neat aCN (0.14 g, 2.8 mmol) was added to the above reaction mixture in one portion and heated the reaction mixture at 50 °C for 2 days. Reaction mixture was concentrated under vacuum to remove most of the ethanol. The crude mixture was extracted with CHCI₃ (50 x 3 mL). The combined organic layer was washed with water, dried over a₂S04, filtered, concentrated and purified by flash chromatography to obtain 1 and 2 as solids.

Compound 1: 'H NMR (300 MHz, CDC1₃): δ 7.77 (s, 1H), 7.26 - 7.35 (m, 1H), 7.00 (t, J= 5.76 Hz, 2H), 4.57 (t, J= 9.88 Hz, 2H), 4.32 - 4.39 (m, 1H), 3.85 - 4.09 (m, 5H), 3.60 (d, J= 11.34 Hz, 1H), 3.34 (s, 3H), 2.63 - 2.74 (m, 1H), 2.02 - 2.15 (m, 1H), 1.31 (s, 9H).

Compound 2: ^XH NMR (300 MHz, CDC1₃): δ 7.28 - 7.36 (m, 2H), 7.00 (t, J= 5.85 Hz, 2H), 4.55 (d, J= 8.97 Hz, 2H), 4.37 (dd, J= 2.65, 11.25 Hz, 1H), 3.88 - 4.07 (m, 5H), 3.60 (d, J = 1 1.34 Hz, 1H), 2.71 (td, J= 3.45, 12.49 Hz, 1H), 1.97 - 2.12 (m, 1H), 1.31 (s, 9H).; Molecular Formula: C₂2H₂5F_{2 5}0₃; LCMS purity: 94.48%; Expected: 445.2; Observed: 446.0 (M+l). (*Preparation of M3: M3.PI1SO₃H (1.0 g, 2.8 mmol) was dissolved in minimum volume of MeOH:CHCl₃ (1 : 1) and passed through a column [Orochem 5 g, 10 ml, Amino (NH₂)] using MeOH as eluent. Organics were concentrated under vacuum to get free M3, which was used directly without further purification.) Synthesis of compound 3 (Step 2):

To a solution of compound 2 (0.40 g, 0.89 mmol) in THF (5 mL) under ₂ atmosphere at -78 °C was added a solution of MeMgBr (0.89 mL, 2.6 mmol, 3M in Et₂0). The reaction mixture was allowed to attain room temperature over 1 hour. TLC shows complete conversion. The reaction mixture was again cooled to -10 °C and quenched with saturated aq. NH4CI solution (10 mL). The reaction mixture was extracted with CH₂CI₂ (50 x 3 mL).

Combined organics were dried over Na₂S0₄, filtered, concentrated and purified by reversed phase chromatography to obtain 3 as di-TFA salt.

Molecular Formula: C22H2₈F2 4O₃; LCMS purity: 88.82%; Expected: 434.2; Observed: 435.2 (M+l).

Synthesis of Example 2 (Step 3):

To a solution of compound 3 (35 mg, 0.053 mmol) in CH₂CI₂ (2 mL) was added TFA (0.5 mL) dropwise at 0 °C. Reaction mixture was allowed to attain room temperature over 2 hours time. TLC shows complete conversion. Reaction mixture was concentrated to dryness. The solid residue was washed with Et₂0 (10 x 3 mL) and dried under vacuum to obtain Example 2 as tri-TFA salt.

^XH NMR (400 MHz, CD₃OD): δ 7.60 (s, 1H), 7.37 (dd, J= 5.02, 8.03 Hz, 1H), 7.22 - 7.31 (m, 2H), 4.70 (d, J= 10.04 Hz, 1H), 4.48 - 4.61 (m, 4H), 4.17 (dd, J= 2.26, 11.29 Hz, 1H), 3.91 (d, J = 11.04 Hz, 1H), 3.73 - 3.83 (m, 1H), 2.54 - 2.62 (m, 1H), 2.22 (t, J= 12.05 Hz, 1H), 1.71 (s, 3H).; Molecular Formula: C17H2₀F2 4O; HPLC purity: 94.98%; Expected: 334.2; Observed: 335.2 (M+l).

SCHEME 3

Example 3

Synthesis of 1 & 2: (Step 1)

To a suspension of M2 (0.95 g, 2.8 mmol) in water (8.67 mL) was added sodium metabisulfite (0.55 g, 2.8 mmol) and stirred a room temperature for lhour. A solution of M3* (0.52 g, 2.8 mmol) in ethanol (8.67 mL) was added to the above reaction mixture and continued the stirring for further 4 hours. Neat aCN (0.14 g, 2.8 mmol) was added to the above reaction mixture in one portion and heated the reaction mixture at 50 °C for 2 days. Reaction mixture was concentrated under vacuum to remove most of the ethanol. The crude mixture was extracted with CHCI₃ (50 x 3 mL). The combined organic layer was washed with water, dried over a₂S04, filtered, concentrated and purified by flash chromatography to obtain 1 and 2 as solids.

Compound 1: 'H NMR (300 MHz, CDC1₃): δ 7.77 (s, 1H), 7.35 - 7.26 (m, 1H), 7.00 (t, J= 5.76 Hz, 2H), 4.57 (t, J= 9.88 Hz, 2H), 4.39 - 4.32 (m, 1H), 4.09 - 3.85 (m, 5H), 3.60 (d, J= 1 1.34 Hz, 1H), 3.34 (s, 3H), 2.74 - 2.63 (m, 1H), 2.15 - 2.02 (m, 1H), 1.31 (s, 9H).

Compound 2: ^XH NMR (300 MHz, CDC1₃): δ 7.36 - 7.28 (m, 2H), 7.00 (t, J= 5.85 Hz, 2H), 4.55 (d, J= 8.97 Hz, 2H), 4.37 (dd, J= 2.65, 11.25 Hz, 1H), 4.07 - 3.88 (m, 5H), 3.60 (d, J= 1 1.34 Hz, 1H), 2.71 (td, J= 3.45, 12.49 Hz, 1H), 2.12 - 1.97 (m, 1H), 1.31 (s, 9H).; Molecular Formula: C₂2H₂5F_{2 5}0₃; LCMS purity: 94.48%; Expected: 445.2; Observed: 446.0 (M+l).

(*Preparation of M3: M3.PI1SO₃H (1.0 g, 2.8 mmol) was dissolved in minimum volume of MeOH:CHCl₃ (1 : 1) and passed through a column [Orochem 5 g, 10 ml, Amino (NH₂)] using MeOH as eluent. Organics were concentrated under vacuum to get free M3, which was used directly without further purification.) Synthesis of compound 3 (Step 2):

To a solution of 2 (0.40 g, 0.89 mmol) in THF (5 niL) under 2 atmosphere at -78 °C was added a solution of MeMgBr (0.89 mL, 2.6 mmol, 3M in Et20). The reaction mixture was allowed to attain room temperature over 1 hour. TLC shows complete conversion. The reaction mixture was again cooled to -10 °C and quenched with saturated aq. NH4CI solution (10 mL). The reaction mixture was extracted with CH2CI2 (50 x 3 mL). Combined organics were dried over Na₂S0₄, filtered, concentrated and purified by reversed phase chromatography to obtain 3 (0.05 g, 8.4%) as di-TFA salt.

Molecular Formula: C22H2₈F2 4O₃; LCMS purity: 88.82%; Expected: 434.2; Observed: 435.2 (M+l).

Synthesis of compound 4 (Step 3):

To a suspension of NaH (22 mg, 0.55 mmol) in dry THF (0.1 mL) under nitrogen atmosphere at 0 °C was added a solution of 3 (120 mg, 0.27 mmol) in dry THF (4.8 mL). The reaction mixture was allowed to come to room temperature and continued the stirring for 2 hours. Reaction mixture was again cooled to 0 °C. Methanesulfonyl chloride (0.42 mL, 0.55 mmol) was added to the reaction mixture and continued the stirring for another 1 hour. The reaction mixture was quenched with water and extracted with EtOAc (3 x 50 mL). Combined organics were dried over Na₂S0₄, filtered, concentrated under vacuum and purified by silica gel chromatography afforded 4 as off white solid.

Molecular Formula: C2₃H₃₀F2N4O5S; LCMS purity: 95.64%; Expected: 512.2; Observed: 513.2 (M+l). Synthesis of Example 3: (Step 4)

To a stirred solution of compound 4 (9.0 mg, 0.017 mmol) in CH2CI2 (2.0 mL) was added TFA (0.2 mL) dropwise at 0 °C. Reaction mixture was allowed to attain room temperature over 2 hours time. TLC shows complete conversion. Reaction mixture was concentrated to dryness. The solid residue was washed with Et₂0 (2 x 10 mL) and dried under vacuum. The solids were once again washed with a mixture of CH2CI2 (0.1 mL) and Et₂0 (5.0 mL) to obtain Example 3 (8.0 mg, 72.7%) as di-TFA salt. The IC50 value of Example 3 is 4nM. ¾ NMR (400MHz ,CD₃OD): δ 7.96 (s, 1 H), 7.41 - 7.31 (m, 1 H), 7.30 - 7.19 (m, 2 H), 4.68 - 4.60 (m, 1 H), 4.22 - 4.07 (m, 4 H), 4.01 (d, J= 11.0 Hz, 1 H), 3.77 (d, J= 11.0 Hz, 1 H), 3.74 - 3.63 (m, 1 H), 3.39 (s, 3 H), 2.43 (d, J= 10.8 Hz, 1 H), 2.04 (t, J= 11.9 Hz, 1 H), 1.51 (s, 3 H).; Molecular Formula: C1₈H22F2 4O₃S; HPLC purity: 95.01%; LCMS mass Expected: 412.2;

Observed: 413.0 (M+l).

PAPER

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00267

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00267

Development of a convergent synthesis of omarigliptin (MK-3102) suitable for commercial manufacture is described. The target molecule is assembled through a diastereoselective reductive amination of a highly functionalized pyranone with a mesylated pyrazole followed by deprotection of a Boc group. The synthesis of the pyranone relies on three Ru-catalyzed reactions: (1) a DKR reduction of a rac-α-aminoketone to set the two contiguous stereogenic centers, (2) a cycloisomerization of a bis-homopropargylic alcohol to a dihydropyran, and, finally, (3) a Ru-catalyzed oxidation of a pyranol to the desired pyranone. The regioselective synthesis of a N-Boc-1-mesyl pyrazole fragment was achieved via base-promoted mesyl group isomerization to afford 30:1 selectivity. A highlight of the endgame process development is telescoping a Boc deprotection and reductive amination followed by direct crystallization of the penultimate from the reaction mixture. This avoids handling of an unstable, mutagenic 1-mesylpyrazole BSA salt used in the earlier multikilogram deliveries and improves the overall diastereoselectivity and efficiency of the route.

Tesfaye Biftu et al, Omarigliptin (MK-3102): A Novel Long-Acting DPP-4 Inhibitor for Once-Weekly Treatment of Type 2 Diabetes;Journal of Medicinal Chemistry, Articles ASAP, March 24, 2014,DOI: 10.1021/jm401992e

Zacuto, Michael J. et al, Process for preparing chiral dipeptidyl peptidase-IV inhibitors;PCT Int. Appl., WO2013003250

Biftu, Tesfaye et al, Novel tetrahydropyran analogs as dipeptidyl peptidase IV inhibitors: Profile of clinical candidate (2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine, Bioorganic & Medicinal Chemistry Letters, 23(19), 5361-5366; 2013

Biftu, Tesfaye et al, Preparation of aminotetrahydropyrans as dipeptidyl peptidase IV inhibitors for the treatment or prevention of diabetes,PCT Int. Appl., WO2011028455

Biftu, Tesfaye et al, Preparation of aminotetrahydropyrans as dipeptidyl peptidase IV inhibitors for treatment or prevention of diabetes,U.S. Pat. Appl. Publ., US20100120863

Biftu, Tesfaye et al, Preparation of aminotetrahydropyrans as dipeptidyl peptidase IV inhibitors for treatment or prevention of diabetes,U.S. Pat. Appl. Publ., US20100120863

Xu, Feng et al, Process for preparation of chiral trans-2,3-disubstituted 5-oxotetrahydropyrans from ethyl N-(diphenylmethylene)glycinate and propargyl besylate, U.S. Pat. Appl. Publ., US20090187028

Ru(p-cymene)-N-sulfonyl-l,2-diphenylethylenediamine (DPEN) catalyst
R. Noyori, et al., J. Org. Chem., 66: 7931-7944 (2001)
B. Mohar, et al., Chem. Commun., 2572-2573 (2001)

The rhodium-catalyzed cycloisomerization
B. Trost etal., J.Amer. Chem.Soc., 125:7482-7483 (2003).

The ruthenium-catalyzed cycloisomerization
B. Trost, et al., J. Amer. Chem. Soc., 124: 2528-2533 (2002)

Gantz, I.; Chen, M.; Mirza, A.; Suryawanshi, S.; Davies, M. J.; Goldstein, B. J. Effect of MK-3102, a novel once-weekly DPP-4 inhibitor, over 12 weeks in patients with type 2 diabetes mellitus. Presented at the 48th Annual Meeting of the European Association for the Study of Diabetes (EASD), Berlin, Germany, October 2012; Abstract 101 (Clinical Research, Metabolism, Merck Research Laboratories).

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