One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases

One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03023H, Communication

P. Matzel, M. Gand, M. Hohne
Imine reductases (IREDs) show great potential as catalysts for reductive amination of ketones to produce chiral secondary amines.

One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases

Imine reductases (IREDs) show great potential as catalysts for reductive amination of ketones to produce chiral secondary amines. In this work, we explored this potential and synthesized the pharmaceutically relevant (R)-rasagiline in high yields (up to 81%) and good enantiomeric excess (up to 90% ee) from the ketone precursor. This one-step approach in aqueous medium represents the shortest synthesis route from achiral starting materials. Furthermore, we demonstrate for the first time that tertiary amines also can be accessed by this route, which provides new opportunities for eco-friendly enzymatic asymmetric syntheses of these important molecules.

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03023H?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases

P. Matzel,^a   M. Gand^b and   M. Höhne*^a  

*Corresponding authors

^aInstitute of Biochemistry, Greifswald University, Felix-Hausdorff-Str. 4, 17487 Greifswald, Germany
E-mail: Matthias.Hoehne@uni-greifswald.de

^bBiocenter Klein Flottbek, University of Hamburg, Ohnhorststr. 18, 22609 Hamburg, Germany

Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03023H

    

 

////////////One-step, asymmetric synthesis,  (R)- ,  (S)-rasagiline,  reductive amination,  imine reductases

(3aS, 6aR)-3-Oxyhexahydrofuro [2, 3-b] furan

(3aS, 6aR)-3-Oxyhexahydrofuro [2, 3-b] furan

809286-93-9 cas

[ Molecular Formula ]:	C6H8O3
[ Molecular Weight ]:	128.12600

(6): Under a nitrogen atmosphere, a, solution containing 440 mg (3.38 mmol) (3S, 3aS, 6aR)-3-hydroxy-hexahydrofuro [2, 3-b] furan (5), 599 mg (5.11 mmol) 4-methylmorpholine-N-oxide, and 2 g 4 A molecular sieves in CH₂Cl₂ (30 mL) was stirred for 20 minutes. Then, tetrapropylammonium perruthenate (36 mg (0.10 mmol)) was added at room temperature. After 5-10 minutes, the reaction mixture was filtered through a pad of silica gel (5 g) with CH₂Cl₂ (100 mL). After evaporation, column chromatography (silica gel 70 g, ethyl acetate in hexanes 40%) gave compound (6) (409 mg. 94%) as a colorless solid, R_f=0.3, [α]²⁵_D -126.6°, c 0.8, CHCl₃, 

IR (Neat) 1758, 1658, 1023 cm^-1;

 ¹H-NMR (400 MHz, CDCl₃) δ: 2.23 (m_c, 1H), 2.96 (dd, 1H, J=6.8 Hz, J=6.8 Hz), 3.79 (m_c, 1H), 3.99 (m, 1H), 4.11 (s, 2H), 6.02 (d, 1H, J=5.0 Hz).

 ¹³C-NMR (100.6 MHz, CDCl₃, Dept) δ: 30.38 (-), 49.58 (+), 67.65 (-), 71.69 (-), 107.89 (+), 215.52 (quat). 

C₆H₈O₃;

Exact Mass: 128.05; Mol. Wt.: 128.13; C, 56.24, H, 6:29, 0, 37.46.

https://www.google.com/patents/US20040127727

/////////////

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol , Furofuranol

CAS :	156928-09-5
Molecular Formula:	C6H10O3
Molecular Weight:	130.144

• Furo[2,3-b]furan-3-ol, hexahydro-, [3R-(3α,3aβ,6aβ)]-
• (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol
• 3R,3AS,6aR-hexahydrofuro[2,3-b]furan-3-ol
• R,S,R-Bisfuran alcohol

WO2012075122  SP ROT= -13.2/1G/100ML, METHANOL

PATENT

http://www.google.com.ar/patents/WO2012070057A1?cl=en

The overall synthesis of the present invention is shown in the scheme 1:

Yet another aspect of present invention is to provide a process for the preparation of compound formula I as per below scheme 2.

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (7) as clear oil (7.8 g, 96.8 A% purity by GC-MS, 55.7 mmol, 74% yield). C₆H₁₀O₃, GC-MS (EI): m/z 100 (M- H₂CO).

¹H NMR (CDCl₃): 1.88 (m, 1H), 2.08 (bd, 1H, −OH), 2.31 (m, 1H), 2.87 (m, 1H), 3.64 (dd, J = 9.2, 7.0 Hz, 1H), 3.87–4.02 (abx system, 3H), 4.45 (m, 1H), 5.70 (d, J = 5.2 Hz, 1H).

¹³C NMR (CDCl₃): 109.54, 73.15, 71.00, 69.90, 46.58, 24.86.

Diastereomeric ratio of 7 to 12 = 98.2:1.8.

GC retention time of 7= 3.20 min; 12 = 3.09 min.

A practical synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol—a key intermediate in the synthesis of darunavir—from monopotassium isocitrate is described. The isocitric acid salt, obtained from a high-yielding fermentation fed by sunflower oil, was converted in several steps to a tertiary amide. This amide, along with the compound’s ester functionalities, was reduced with lithium aluminum hydride to give, on acidic workup, a transient aminal-triol. This was converted in situ to the title compound, the bicyclic acetal furofuranol side chain of darunavir, a protease inhibitor used in treatment of HIV/AIDS. Key to the success of this process was identifying an optimal amide that allowed for complete reaction and successful product isolation. N-Methyl aniline amide was identified as the most suitable substrate for the reduction and the subsequent cyclization to the desired product. Thus, the side chain is produced in 55% overall yield from monopotassium isocitrate.

Practical Synthesis of the Bicyclic Darunavir Side Chain: (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol from Monopotassium Isocitrate

Gary L. Moore, Rodger W. Stringham, David S. Teager, and Tai-Yuen Yue^* 

Clinton Health Access Initiative, 800 North Five Points Road, West Chester, Pennsylvania 19380, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00377, http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00377

 

*E-mail address: tyue@clintonhealthaccess.org.

1H NMR PREDICT

 

 

13C NMR PREDICT

 

 PATENT

WO2004033462

In particular, the following synthetic scheme (1) illustrates the present commercial method of synthesizing compound (I) . This synthesis is disclosed in detail in A.K. Ghosh et al . , Tetra- hedron Letters, 36 (4) , pp. 505-508 (1995), incorporated herein by reference. Also see, A.K. Ghosh et al., J. Med. Chem . , 39, pp. 3278-3290 (1996) for the synthesis of compound (I) and a related compound of structural formula (II) (i.e., (3S, 3aR, 7aS) -3- hydroxyhexahydrofuro [2, 3-b] pyran) .

Scheme 1 (prior art)

(91%)
Cobaloxime (catalytic) , NaBH₄, EtOH

Alternatively,
-OAc
0 Immobilized Lipase 30
0- pH 7 buffer 23°C, 24 h
⁽+⁾

R=Ac
MeLi, THF
^ R=H (Compound (I))

The present method of synthesizing bis-THF is summarized as follows:

<

(78-100%;

(70-90%)

(65-80%;

2. NaBH₄, EtOH (65-75%) -15°C, 1-3 h Compound (I) (bis-THF) Another aspect of the present invention is to provide a method of preparing a compound having a structure

then utilizing the benzyl-protected 5-hydroxymethyl- 5H-furan-2-one in the synthesis of compound (I) .

Another aspect of the present invention is to provide a method of preparing compounds related to bis-THF by using a starting material having a following structure:

X

I

R R

The synthesis of bis-THF (compound (I) ) is summarized below:

(1) (2)

(3)

15) (6)

(I)

(3R, 3aS , 6aR) -3-Hydroxyhexahydrofuro [2 , 3-b] uran (I)

(3R, 3aS, 6aR) -3-Hydroxyhexahydrofuxo [2, 3- b] furan (I) : To a solution containing 250 mg (1.95 mmol) (3aS, 6aR) -3-oxyhexahydrofuro [2, 3-b] furan (6) in EtOH (25 mL) was added '89 mg (2.35 mmol) NaBH₄ at -18 °C. The reaction mixture was stirred at -18 °C for 2.5 hours, then the reaction was quenched with saturated NH₄C1 solution (5 mL) and warmed to room temperature. The resulting mixture was concentrated under reduced pressure, and then 10 mL water was added. The aqueous layer was extracted with ethyl acetate (3 x 50 mL) and a solution of 70% CHC1₃, 20% MeOH, and 10% water (3 x 50 mL) . The combined organic extracts were dried over Na₂S0₄. Column chromatography (silica gel 80 g, MeOH in CHC1₃ 7%) gave compound (I) (178 mg. 70%) as a colorless solid, R_f=0.3, [α]²⁵ _D -12.4°, c 1.3, MeOH. IR (neat) 2951, 1641, 1211 cm^"1; ^XH-NMR (400 MHz CDC1₃) δ: 1.85 (m_c, IH) , 1.94 (bs, IH) , 2.27 (m_c, IH) , 2.84 (m_c, IH) , 3.63 (dd, IH, J=7.1 Hz, J=9.2 Hz), 3.89 (m_c, IH) , 3.97 (m_c, IH) , 4.43 (dd, IH, J=6.8 Hz, J=14.5 " Hz), 5.68 (d, IH, J=5.2 Hz). ¹³C-NMR (125.8 MHz, CDC1₃, Dept) δ^': 25.27 (-) , 46.97 (+) , 70.31 (-) , . 71.26 (-), 73.50 (+) , 109.93. (+) . C₆H₁₀O₃; Exact Mass: 130.06; Mol. Wt . : 130.14; C, 55.37, H, 7.74, 0, 36.88.

Experimentals :

l-(Benzyloxy)-but-3-en-2-ol (±)-(8): To a solution of vinylmagnesium bromide (1 M in THF, 40 mL, 40 mmol) in THF (10 mL) at 0°C was added benz- yloxyacetaldehyde (7) (5 g, 33.3 mmol) dropwise. The mixture was stirred for 10 min at 0°C, and the reaction then was quenched with 20 L of saturated NaHC0₃ solution. The layers were separated, the aqueous layer was extracted with ethyl acetate (3 x 20 mL) , and the combined organic extracts were dried over sodium sulfate. Evaporation of solvent under reduced pressure, followed by column chromatography on silica gel (20% EtOAc in hexanes as the eluent) yielded alcohol (±)-8 (5.22 g, 88%) as a yellow oil, R_f=0.40 (30% EtOAc in hexanes); ¹H-NMR (400 MHz, CDC1₃) δ: a 2.79 (bs, IH) , 3.39 (dd, IH, J=1.7, 7.85 Hz), 3.55 (dd, IH, J=3.35, 6.3 Hz), 4.35 (m, IH) , 4.58 (s, IH) , 5.21 (dt, IH, J=7.75, 1.4 Hz), 5.38 (dt, IH, J=14.18, 1.4 Hz), 5.84 (m, IH) , 7.30-7.38 (m, 5H) ; ¹³C-NMR (100.6 MHz, CDC1₃) δ: 71.52, 73.37, 74.02, 116.49, 127.85, 128.49, 136.58, 137.81. (S)-l-(Benzyloxy) -but-3-en-2-ol (9) and (R) -1- (benzyloxy) -but-3-en-2-oyl acetate (10):

A: To a solution of alcohol (±)-(8) (5.21 g, 29.3 mmol) in acetic anhydride (14 mL, 147 mmol) and tert-butyl methyl ether (70 mL, 586 mmol) was added immobilized lipase PS-30 (5.3 g ) on Celite 521 (Aldrich) . The mixture was stirred at room temperature for 20 h, and then filtered through Celite. Removal of solvent under reduced pressure followed, by column chromatography on silica gel (10 and 15% EtOAc in hexanes as the eluents) yielded acetate (10) (3.81 g, 54%) R_f=0.57 (30% EtOAc in hexanes) as a clear oil, [of]²⁵ _D -2° (c 1, CHC1₃) ; NMR (500 MHz, CDC1₃) δ: 2.10 (s, 3H) , 3.55-3.59 (m, 2H) , 4.56 (q, 2H, J=12.2, 14.0 Hz), 5.24 (d, IH, J-10.6 Hz), 5.32 (d, IH, J=17.3 Hz), 5.50 (m, IH) , 5.84 (m, IH) , 7.25-7.36 (m, 5H) ; ¹³C-NMR (125.8 MHz, CDC1₃) δ: 21.62, 71.67, 73.57, 73.59, 118.39, 128.14, 128.84, 133.77, 138.32, 170.63; alcohol 9 (2.34 g, 45%) as a yellow oil, R_f=0.40 (30% EtOAc in hexanes), [α]²⁵ _D- 8.3° (c 1.06, MeOH) .

B: To a solution of alcohol (±)-(8) (3.92 g, 22.0 mmol) in vinyl acetate (46 mL, 499 mmol) and ethylene glycol dimethyl ether (46 mL, 440 mmol) was added immobilized lipase PS-30 (4 g ) on Celite-545 (Aldrich) . The mixture was stirred at room temperature for 28 h, and then filtered through celite. Removal of solvent under reduced pressure, followed by column chromatography on silica gel (10 and 15% EtOAc in hexanes as the eluents) yielded acetate

(10) (2.20 g, 45%) R_f=0.57 (30% EtOAc in hexanes) as a clear oil, [ ]²⁵ _D -2.7° (c 1.35, MeOH); alcohol (9) (2.00 g, 51%) as a yellow oil, R_f=0.40 (30% EtOAc in hexanes), [α]²⁵ _D -11.4° (c 1.6, MeOH).

C: To a solution of alcohol (+)-(8) (30 mg, 0.168 mmol) in isopropenyl acetate (375 μL, 3.36 mmol) and ethylene glycol dimethyl ether (375 μL, 3.61mmol) was added immobilized lipase PS-30 (35 mg) on Celite-545 (Aldrich) . The mixture was stirred at room temperature for 23 h, and then filtered through celite. Removal of solvent under reduced pressure, followed by column chromatography on silica gel (10) and 15% EtOAc in hexanes as the eluents) yielded acetate 10 (20.3 mg, 54%) as an oil, R_f=0.57 (30% EtOAc in hexanes), [α]²⁵ _D -1.4° (c 1.02, MeOH); alcohol (9) (13 mg, 43%) as a yellow oil, R_f=0.40

(30% EtOAc in hexanes), [ ]²⁵ _D -13.5° (c 1.3, MeOH). (R) -1- (Benzyloxy) -but-3-en-2-ol (11): To a solution of acetate (10) (3.7 g, 16.9 mmol) in methanol (20 mL) was added K₂C0₃ (7 g, 50.6 mmol). The mixture was stirred at room temperature for 35 min. Methanol then was removed under reduced pressure. The resulting solid residue was dissolved in ethyl acetate, washed with saturated NH₄C1 solution and brine, and dried over sodium sulfate. Removal of ethyl acetate under reduced pressure yielded the crude alcohol (11) (3 g, 100%) as a yellow oil, R_f=0.40 (30% EtOAc in hexanes), [α]²⁵ _D 8.3° (c 1.06, MeOH) .

(S)-l- (Benzyloxy) -but-3-en-2-ol (9) from (11): To a solution of crude alcohol (5) (2 g, 11.2 mmol), triphenylphosphine (5.88 g , 22.4 mmol), and 4-nitrobenzoic acid (2.81 g, 16.8 mmol) in benzene (35 mL) was added at room temperature diisopropyl azodicarboxylate (4.35 mL, 22.4 mmol) dropwise. The mixture was stirred for 40 min, followed by the re- moval of solvent under reduced pressure. All of the crude ester then was dissolved in a mixture of MeOH:Et₃N:H₂0 (20ml) in the ratio of 4:3:1 and reacted with LiOH (1.64 g, 39.3 mmol) at room temperature. The mixture was stirred for 2 h, followed by the removal of solvent. Column chromatography on silica gel (15% EtOAc in hexanes as the eluent) yielded alcohol (3) (1.64 g, 82%) as a yellow oil, R_f=0.40 (30% EtOAc in hexanes), [o;]²⁵ _D -7.3° (c 0.82, MeOH) . (S) -1- (Benzyloxy) -but-3-en-2-yl acrylate

(12): To a solution of alcohol (3) (1 g, 5.61 mmol) in CH₂C1₂ (20 L) was added acryloyl chloride (685 μL, 8.41 mmol) dropwise, followed by the addition of Et₃N (1.56 mL, 11.2 mmol). The resulting mixture was stirred for 10 min, and the solvent then was removed under reduced pressure. Filtration of the concentrated crude acrylate through a pad of silica gel using 15% EtOAc in hexanes, followed by the removal of solvent, yielded acrylate (12) (1.19 g, 92%) as a colorless oil, R_f=0.57 (30% EtOAc in hexanes), [α]²⁵ _D -5.7° (c 1.09, CHC1₃) ; ¹H-NMR (500 MHz, CDC1₃) δ: 3.59-3.65 (m, 2H) , 4.56 (q, 2H, J=12.2, 14.65 Hz), 5.25 (d, IH, J=10.6 Hz), 5.33 (d, IH, J=16.8 Hz), 5.57 (m, IH) , 5.84-5.91 (m, 2H) , 6.17 (dd, IH, J=6.9, 10.4 Hz), 6.44 (dd, IH, J=1.3, 16.2 Hz), 7.27-7.36 (m, 5H) ; ¹³C-NMR (125.8 MHz, CDC1₃) δ: 71 . 62 , 73 . 58 , 73 . 77 , 118 . 49 , 128 . 05 , 128 . 85 , 131 . 52 , 133 . 62 , 138 . 31 , 165 . 79 .

(5S) -5- (Benzyloxymethyl) -5H-furan-2-one (13): To a solution of acrylate (12) (1.87 g, 8.05 mmol) in CH₂C1₂ (700 mL) was added second generation Grubbs' catalyst (4 mol %, 170 mg, 0.322 mmol). The reaction mixture was refluxed for 5 hours, and the solvent then was removed under reduced pressure. Column chromatography on silica gel (30% EtOAc in hexanes as the eluent) yielded the furanone (13)

(1.62 g, 98%) as a brown oil, R_f=0.15 (30% EtOAc in hexanes), [α]²⁵ _D -81.3° (c 1.09, MeOH); ^αH-NMR (500 MHz, CDC1₃) δ: 3.66 (dd, IH, J=5.0, 5.5 Hz), 3.71 (dd, IH, J=5.0, 5.2 Hz), 4.57 (s, 2H) , 5.17 (m, IH) , 6.16 (dd, IH, J=1.9, 3.8 Hz), 7.29-7.37 (m, 5H) , 7.48 (dd, IH, J=1.4, 4.3 Hz); ¹³C-NMR (125.8 MHz, CDC1₃) δ: a 69.86, 74.18, 82.61, 123.03, 128.42, 128.95, 137.69, 154.32, 173.19.

(4S ,5S) -5- (Benzyloxymethyl) -4- [1 , 3] di- oxolan-2-yldihydrofuran-2-one (14) : A solution of furanone (13) (1.2 g, 5.88 mmols) and benzophenone

(108 mg, 0.588 mmols) in [1, 3] -dioxolane (108 mg) was degassed for 40 min in a stream of argon. The mixture then was irradiated using one 450 watt ACE glass medium pressure mercury lamp, from a distance of 15 cm, for 9 hours. Progress of this reaction was observed via ¹H-NMR. As the reaction mixture was degassed, and throughout all of the irradiation time, the reaction flask was held in a water cooled cooling mantel. The temperature of the cooling water was constantly maintained near 0°C. Upon completion of the reaction, solvent was removed under reduced pressure, followed by column chromatography on silica gel (35% EtOAc in hexanes as the eluent), yielding the title compound (1.34 g, 82%) as a clear oil, R_f=0.14 (30% EtOAc in hexanes), [α]²⁵ _D 16.5° (c 1.2, CHC1₃) ; ¹H-NMR (500 MHz, CDC1₃) δ: 2.50 (dd, IH, J=3.9, 12.9 Hz), 2.70-2.79 (m, 2H) , 3.58 (dd, IH, J=3.5, 7.2 Hz), 3.75 (dd, IH, J=2.8, 7.9 Hz), 3.87-3.92 (m, 2H) , 3.97-4.00 ( , 2H) , 4.51 (d, IH, J=11.9 Hz), 4.57-4.61 (m, 2H) , 4.88 (d, IH, J=3.6 Hz), 7.26-7.36 (m, 5H) ; ¹³C-NMR (125.8 MHz, CDC1₃) δ: 30.39, 40.53, 65.77, 71.74, 73.99, 79.52, 104.14, 128.00, 128.89, 138.07, 176.79.

(4S,5S) -4-[l,3]Dioxolan-2-yl-5-hydroxy- methyldihydrofuran-2-one (15) : To a solution of dihydrofuranone (14) (0.5 g, 1.79 mmol) in MeOH (30 mL) was added Pd/C (25 mg) . The mixture was stirred at room temperature under an H₂ balloon for 24 hours, and then filtered over Celite. Removal of solvent under reduced pressure, followed by column chromatography on silica gel (35% EtOAc in hexanes as the eluent) yielded the compound (15) (301 mg, 89%) as a white solid, R_f=0.28 (50% EtOAc in hexanes), [ ]²⁵ _D 22° (c 1.32, CHC1₃) ; ^XH-NMR (500 MHz, CDC1₃) δ: 2.54 (dd, IH, J=6.0, 11.4 Hz), 2.68-2.81 (m, 2H) , 3.66

(dd, IH, J=3.9-8.5 Hz), 3.88-3.95 (m, 3H) , 3.97-4.02 (m, 2H) , 4.53 (m, IH) , 4.91 (d, IH, J=3.9 Hz); ¹³C- NMR (125.8 MHz, CDC1₃) δ: 30.68, 40.12, 64.36, 65.77, 81.07, 103.94, 176.83. (3S , 3aS , 6aR) -3-Hydroxyhexahydrofuro [2 , 3- b] furan (5) : To a solution of lithium aluminum hydride (76 mg, 1.98 mmols) in THF (10 ml) at 0°C was added dihydrofuranone 15 (275 mg , 1.46 mmol) in THF (30 mL ) dropwise. Upon completion of the reduction after 4 hours, the reaction was quenched with a saturated aqueous sodium sulfate solution at 0°C. The solvent then was decanted and the remaining residue was washed with THF (3x) , EtOAc (3x) , and CHC1₃ (3x) . The organic extracts were combined and the solvent was removed under reduced pressure, yielding a crude (2S, 3S) -3- [1, 3] dioxolan-2- ylpentane-1, 2, 5-triol, which was immediately used in the next reaction.

The crude triol was dissolved in a mixture of THF:H₂0 (8ml) in the ratio of a 5:1. This solu- tion then was acidified at room temperature to pH 2- 3 with 1 N hydrochloric acid, and was stirred for 40 hours. Removal of solvent with the aid of benzene under reduced pressure, followed by column chromatography purification on silica gel (5% MeOH in CHCI₃ as the eluent) yielded the compound (5) (145 mg,

77%) as a white solid, R_f=0.40 (15% MeOH in CHC1₃) , [α]²⁵ _D -25.1° (c 1.05, CHC1₃) ; ^XH-NMR (500 MHz, CDCI3) δ: 1.67 ( , IH) , 2.13 (m, IH) , 2.31 (bs, IH) , 2.79 (m, IH) , 3.80-3.88 (m, 3H) , 3.95 (dd, IH, J=3.2, 7.1 Hz), 4.20 (d, IH, J=3.1 Hz), 5.86 (d, IH, J=4.9 Hz). Preparation of bis-THF derivative (I) (by Mitsunobu inversion of compound (5) ) : To a stirred solution of alcohol (5) (400 mg, 3.07 mmol), tri- phenylphosphine (1.6 g, 61.4 mmol), and p-nitroben- zoic acid (770 mg, 4.61 mmol) in dry benzene (30 mL) at 23 °C was added diisoproylazodicarboxylate (DIAD, 1.2 L, 6.14 mmol) dropwise. After 1.5 hours, the mixture was concentrated in vacuo, and the crude ester was dissolved in a (4:3:1) mixture of MeOH:Et₃N:H₂0 (24 mL) , then treated with LiOH (450 mg, 10.7 mmol) . The solution was stirred at room temperature for 2 h. The mixture then was concentrated under reduced pressure and the residue was chromatographed over silica gel to provide the bis-

THF (I) (326 mg, 82%); [ ]²⁵ _D -12.4 (c 1.16 , MeOH)

 

In particular, the following synthetic scheme (1) illustrates the present commercial method of synthesizing compound (I). This synthesis is disclosed in detail in A.K. Ghosh et al., Tetra. hedron Letters, 36 (4) , pp. 505-508 (1995), incorporated herein by reference. Also see, A.K. Ghosh et al., J. Med. Chem . , 39, pp. 3278-3290 (1996) for the synthesis of compound (I) and a related compound of structural formula (II) (i.e., (3S, 3aR, 7aS) -3-hydroxyhexahydrofuro [2, 3-b] pyran).

The present method of synthesizing bis-THF is summarized as follows:

The synthesis of bis-THF (compound (I) ) is summarized below:

 

previously.

REF

1. Ghosh, Arun K.; Journal of Organic Chemistry 2004, 69(23), pg 7822-7829 
2. Kulkarni, Mukund G.; Tetrahedron: Asymmetry 2010, 21(19), pg 2394-2398 
3.  Quaedflieg, Peter J. L. M.; Organic Letters 2005, 7(26), pg 5917-5920 
4.  Black, David M.; Tetrahedron: Asymmetry 2008, 19(17), pg 2015-2019 
5. Ghosh, Arun K.; Synthesis 2006, (18),pg 3015-3018
6. Canoy, Will L.; Organic Letters 2008, 10(6), pg 1103-1106 
7.  Ghosh, Arun K.; ACS Medicinal Chemistry Letters 2011, 2(4), pg 298-302 
8.  Kesteleyn, Bart Rudolf Romanie; WO 2003022853 A1 2003 
9. Yu, Richard H.; Organic Process Research & Development 2007, 11(6), pg 972-980 
10. Khmelnitsky, Yuri L.; Organic Process Research & Development 2011, 15(1), pg 279-283 

//////////(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, furofuranol, DARUNAVIR

O[C@H]1CO[C@H]2OCC[C@@H]12

(S)-2-(4-(Piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide Tosylate Monohydrate

 

 as tosylate H2o

1613220-15-7 cas

free 1038915-60-4

• 2-[4-(3S)-3-Piperidinylphenyl]-2H-indazole-7-carboxamide
• Niraparib
•  Jones, Philip; Journal of Medicinal Chemistry 2009, V52(22), P7170-7185

• MK-​4827

(S)-2-(4-(Piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide Tosylate Monohydrate 1

................... The solid was collected and dried in vacuo at 40 °C to afford 1 as the tosylate monohydrate salt (797 g, 86%, >99 wt %, >99%ee) as a tan-coloured solid.

Mp = 144 °C. ¹H NMR (600 MHz, CD₃OD) δ 8.95 (1H, s), 8.15 (1H, dd, J = 7.1, 1.2 Hz), 8.02 (2H, m), 8.00 (1H, dd, J = 8.3, 1.2 Hz), 7.72 (2H, m), 7.49 (2H, m), 7.25 (1H, dd, J = 8.3, 7.1 Hz), 7.22 (2H, d, J = 8.0 Hz), 3.49–3.43 (2H, m), 3.16–3.04 (3H, m), 2.34 (3H, s), 2.09–2.05 (2H, m), 1.96–1.82 (2H, m).

¹³C NMR (150.9 MHz, CD₃OD) δ 169.7, 148.1, 143.7, 143.0, 141.9, 140.5, 131.8, 130.0, 129.8, 127.3, 127.1, 125.4, 124.2, 123.3, 122.4, 50.2, 45.2, 41.1, 30.9, 24.0, 21.4.

 

 

 

Discovery of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors

Philip Jones*, Sergio Altamura, Julia Boueres, Federica Ferrigno, Massimiliano Fonsi, Claudia Giomini, Stefania Lamartina, Edith Monteagudo, Jesus M. Ontoria, Maria Vittoria Orsale, Maria Cecilia Palumbi, Silvia Pesci, Giuseppe Roscilli, Rita Scarpelli, Carsten Schultz-Fademrecht, Carlo Toniatti and Michael Rowley

IRBM/Merck Research Labs Rome, Via Pontina km 30,600, 00040 Pomezia, Italy

J. Med. Chem., 2009, 52 (22), pp 7170–7185

DOI: 10.1021/jm901188v, http://pubs.acs.org/doi/abs/10.1021/jm901188v?source=chemport

 

*To whom correspondence should be addressed. Current address: Department of Medicinal Chemistry, Merck Research Labs Boston, Avenue Louis Pasteur 33, Boston, MA 02115-5727. Phone: +1-617-992-2292. Fax: +1-617-992-2405. E-mail: philip_jones@merck.com.

Abstract

We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC₅₀ = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC₅₀ = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC₅₀ in the 10−100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.

//////////1613220-15-7, 1038915-60-4, 2-[4-(3S)-3-Piperidinylphenyl]-2H-indazole-7-carboxamide, Niraparib, mk 4827

The transposition of Sandmeyer chlorination from a batch to a safe continuous-flow process was investigated. Our initial approach was to develop a cascade method using flow chemistry which involved the generation of a diazonium salt and its quenching with copper chloride. To achieve this safe continuous process diazotation, a chemometric approach (Simplex method) was used and extrapolated to establish a fully continuous-flow method. The reaction scope was also examined via the synthesis of several (het)aryl chlorides. Validation and scale-up of the process were also performed. A higher productivity was obtained with increased safety.

Efficient Transposition of the Sandmeyer Reaction from Batch to Continuous Process

Joseph D’Attoma^†, Titi Camara^‡, Pierre Louis Brun^‡, Yves Robin^‡, Stéphane Bostyn^*§, Frédéric Buron^*† , and Sylvain Routier^*† 

^† Institut de Chimie Organique et Analytique, Univ Orleans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067 CEDEX 2 Orléans, France

^‡ ISOCHEM, 4 Rue Marc Sangnier, BP 16729, 45300 Pithiviers, France

^§ Institut de Combustion, Aérothermique, Réactivité, et Environnement (ICARE), 1c, Avenue de la Recherche Scientifique, 45071 CEDEX 2 Orléans, France

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00318, http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00318

 

*E-mail: frederic.buron@univ-orleans.fr., *E-mail: sylvain.routier@univ-orleans.fr., *E-mail: stephane.bostyn@univ-orleans.fr.

¹H NMR (250 MHz, Chloroform-d) δ 7.65 (dd, J = 2.1, 0.6 Hz, 1H, H_ar), 7.42 (dd, J = 8.7, 0.6 Hz, 1H, H_ar), 7.32 (dd, J = 8.7, 2.0 Hz, 1H, H_ar).

2,5-Dichloro-1,3-benzoxazole (33)

The reaction was carried out as described in general procedure B using 2-Amino-5-chlorobenzoxazole (221 mg, 1.31 mmol). After purification with silica flash chromatography (EP 100%), the product was isolated as a yellow oil (62 mg, 25%).

CAS number 3621-81-6.

¹H NMR (250 MHz, Chloroform-d) δ 7.65 (dd, J = 2.1, 0.6 Hz, 1H, H_ar), 7.42 (dd, J = 8.7, 0.6 Hz, 1H, H_ar), 7.32 (dd, J = 8.7, 2.0 Hz, 1H, H_ar).

 

¹³C NMR (101 MHz, Chloroform-d) δ 152.27 (C), 150.12 (C), 142.06 (C), 130.79 (C), 125.85 (CH), 119.78 (CH), 111.16 (CH).

 

HRMS [M + H]+ (EI) calcd for C₇H₄Cl₂NO: 187.9664, found: 187.9663.

1H NMR PREDICT

 

13 C NMR PREDICT

 

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