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CARMEGLIPTIN………….a DPP-4 inhibitor

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Figure

(2S,3S,11βS)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11β-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-(4S)-fluoromethyl-pyrrolidin-2-one Dihydrochloride

(2S,3S,11bS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4(S)-fluoromethyl-pyrrolidin-2-one

813452-14-1 (di-HCl)
916069-91-5 (mono-HCl)

Roche…….innovator

 

CARMEGLIPTIN, 813452-18-5, 结构式

 

CARMEGLIPTIN

813452-18-5

(2S,3S,11βS)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11β-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-(4S)-fluoromethyl-pyrrolidin-2-one

(S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl)-4-(fluoromethyl)pyrrolidin-2-one

(S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl)-4-(fluoromethyl)pyrrolidin-2-one
(S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl)-4-(fluoromethyl)pyrrolidin-2-one
分子式: C20H28FN3O3
分子量: 377

813452-18-5, Carmegliptin, R-1579;carmegliptin, Carmegliptin (USAN/INN), SureCN419289, UNII-9Z723VGH7J, CHEMBL591118, CHEBI:699093, Ro-4876904, D08631, R-1579, B1Q

 

Type 2 diabetes is a chronic, progressive metabolic disease, affecting about 4% of the world population. The main goal of the management of type 2 diabetes is to achieve glycemic control as close to the nondiabetic range as practicable, in order to reduce the risk of late-stage complications.However, the therapeutic effect provided by existing medications is often not sustainable, since the multi-organ defects responsible for the disease are only insufficiently addressed.

Dipeptidyl peptidase-IV (DPP-IV) inhibitors have emerged as a new therapeutic option to treat type 2 diabetes.

Their rapid rise in popularity is due to the favourable safety profile (no hypoglycemia, no weight gain, no gastrointestinal problems—typical side effects associated with established anti-diabetic agents). DPP-IV is a ubiquitous serine protease, the inhibition of which prevents the degradation of glucagon-like peptide 1 (GLP-1). The resulting higher levels of GLP-1 have a beneficial impact on major players involved in the pathogenesis of type 2 diabetes: β-cells, liver, α-cells, gut, and brain.

Long-term studies with DPP-IV inhibitors in patients are underway in order to confirm the safety and sustainability of these effects, and, in particular, their ability to prevent the progressive loss of β-cell function.

 

SYNTHESIS

 

Figure

 

aReagents and conditions: a) HCO2Me, Δ; b) POCl3, MeCN; c) HO2CCH2CO2Et, neat, 120 °C; d) ethyl acrylate, neat; e) t-BuOK, neat (5 steps); f) NH4OAc, MeOH; g) NaBH4, TFA, THF; h) Boc2O, CH2Cl2; i) KOH, aq THF; j) DPPA, Et3N, TMSCH2CH2OH, PhMe, 80 °C; k) Et4NF, MeCN; l) chiral HPLC; m) Et3N, CH2Cl2; n) NaH, DMF; o) HCl, dioxane; p) HCl, 2-PrOH.

 

Full-size image (22 K)

Scheme 2.

Reagents and conditions: (a) NH4OAc, MeOH, rt, 95%; (b) NaBH4, TFA, THF, 0 °C; (c) Boc2O, CH2Cl2, 83% over 2 steps; (d) KOH, aq THF, rt; (e) DPPA, Et3N, 2-(trimethylsilyl)ethanol, toluene, 80 °C; (f) Et4NF, CH3CN, 50 °C, 56% over 3 steps; (g) Et3N, CH2Cl2, (h) NaH, cat. NaI, DMF; (i) HCl, 1,4-dioxane.

 

 

Carmegliptin (2.70) is an anti-diabetes drug which is currently in late stage clinical trials. It represents a further structural advancement from the other existing marketed drugs in this class, sitagliptin (2.71, Januvia) and vildagliptin (2.72, Zomelis, Figure 7). These compounds are all members of the dipeptidyl peptidase 4 class (DPP-4), a transmembrane protein that is responsible for the degradation of incretins; hormones which up-regulate the concentration of insulin excreted in a cell. As DPP-4 specifically cleaves at proline residues, it is unsurprising that the members of this drug class exhibit an embedded pyrrolidine ring (or mimic) and additional decoration (a nitrile or fluorinated alkyl substituent is present in order to reach into a local lipophilic pocket). One specific structural liability of the 2-cyano-N-acylpyrrolidinyl motif (2.73) is its inherent susceptibility towards diketopiperazine formation (2.74, Scheme 29) [80], however, one way to inhibit this transformation is to position a bulky substituent on the secondary amine nucleophile as is the case in vildagliptine (2.72).

[1860-5397-9-265-7]
Figure 7: Structures of DPP-4 inhibitors of the gliptin-type.
[1860-5397-9-265-i29]
Scheme 29: Formation of inactive diketopiperazines from cis-rotameric precursors.

A single crystal X-ray structure of carmegliptin bound in the human DPP-4 active site has been published indicating how the fluoromethylpyrrolidone moiety extends into an adjacent lipophilic pocket [81]. Additional binding is provided by π–π interaction between the aromatic substructure and an adjacent phenylalanine residue as well as through several H-bonds facilitated by the adjacent polar substituents (Figure 8).

 

[1860-5397-9-265-8]
Figure 8: Co-crystal structure of carmegliptin bound in the human DPP-4 active site (PDB 3kwf).

The reported synthesis of carmegliptin enlists a Bischler-Napieralski reaction utilising the primary amine 2.76 and methyl formate to yield the initial dihydroquinoline 2.77 as its HCl salt (Scheme 30) [82]. This compound was next treated with 3-oxoglutaric acid mono ethyl ester (2.78) in the presence of sodium acetate. Decarboxylation then yields the resulting aminoester 2.79 which was progressed through an intramolecular Mannich-type transformation using aqueous formaldehyde to allow isolation of enaminoester 2.80 after treatment of the intermediate with ammonium acetate in methanol.

The next step involves a very efficient crystallisation-induced dynamic resolution of the racemic material using the non-natural (S,S)-dibenzoyl-D-tartaric acid ((+)-DBTA). It is described that the desired (S)-enantiomer of compound 2.81 can be isolated in greater than 99% ee and 93% overall yield. This approach is certainly superior to the original separation of the two enantiomers (at the stage of the final product) by preparative chiral HPLC that was used in the discovery route (albeit it should be noted that both enantiomers were required for physiological profiling at the discovery stage).

Next, a 1,2-syndiastereoselective reduction of enaminoester 2.81 occurs with high diastereocontrol imposed by the convexed presentation of the substrate for the formal conjugate addition and subsequent protonation steps. This is followed by Boc-protection and interconversion of the ethyl ester to its amide derivative 2.82 in 80% overall yield for this telescoped process. The primary amide in 2.82 was then oxidised via a modern variant of the classical Hoffmann rearrangement using phenyliodine diacetate (PIDA).

Following extensive investigation it was found that slowly adding this reagent in a mixture of acetonitrile/water to a suspension of amide 2.82 and KOH gave clean conversion to the amine product in high yield. This new procedure was also readily scalable offering a cleaner, safer and more reliable transformation when compared to other related rearrangement reactions. During a further telescoped procedure amine 2.83 was treated with lactone 2.84 to regenerate the corresponding lactam after mesylate formation. Finally, removal of the Boc-group with aqueous hydrochloric acid furnished carmegliptin as its HCl salt.

 

[1860-5397-9-265-i30]
Scheme 30: Improved route to carmegliptin.
  1. Peters, J.-U. Curr. Top. Med. Chem. 2007, 7, 579–595……………..80
  2. Mattei, P.; Boehringer, M.; Di Gorgio, P.; Fischer, H.; Hennig, M.; Huwyler, J.; Koçer, B.; Kuhn, B.; Loeffler, B. M.; MacDonald, A.; Narquizian, R.; Rauber, E.; Sebokova, E.; Sprecher, U.Bioorg. Med. Chem. Lett. 2010, 20, 1109–1113. doi:10.1016/j.bmcl.2009.12.024………..81
  3. Albrecht, S.; Adam, J.-M.; Bromberger, U.; Diodone, R.; Fettes, A.; Fischer, R.; Goeckel, V.; Hildbrand, S.; Moine, G.; Weber, M. Org. Process Res. Dev. 2011, 15, 503–514. doi:10.1021/op2000207……….82

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Org. Process Res. Dev. 2011, 15, 503–514. doi:10.1021/op2000207

http://pubs.acs.org/doi/full/10.1021/op2000207

 

Abstract Image

A short and high-yielding synthesis of carmegliptin (1) suitable for large-scale production is reported. The tricyclic core was assembled efficiently by a decarboxylative Mannich addition−Mannich cyclization sequence. Subsequent crystallization-induced dynamic resolution of enamine 7 using (S,S)-dibenzoyltartaric acid was followed by diastereoselective enamine reduction to give the fully functionalized tricyclic core with its three stereogenic centers. The C-3 nitrogen was introduced by Hofmann rearrangement of amide 28, and the resulting amine 10was coupled with (S)-fluoromethyl lactone 31. Following cyclization to lactam 13 and amine deprotection, 1 was obtained in 27−31% overall yield with six isolated intermediates.

Preparation of (2S,3S,11βS)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11β-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-(4S)-fluoromethyl-pyrrolidin-2-one Dihydrochloride (1)   CARMEGLIPTIN

A suspension of carbamate 13 (136 kg, 285 mol) in a mixture of H2O (112 kg) and acetone (122 kg) was treated at 50 °C within 60 min with 37% aq HCl (98.0 kg). After 90 min at 47−52 °C the solution was polish filtered through a 5 μm filter. The first reactor and the transfer lines were washed with a hot (47−52 °C) mixture of H2O (13.0 kg) and acetone (116 kg). The filtrate was cooled to 25 °C and treated at this temperature within 80 min with acetone (1600 kg) whereupon the product crystallized out. The resulting suspension was stirred for 1 h at 25 °C and subsequently centrifuged. The crystals were washed in two portions with acetone (391 kg) and dried at 50 °C and <30 mbar until constant weight to afford 122.4 kg (95%) of the title compound as colorless crystals with an assay (HPLC) of 98.8% (w/w).
1H NMR (400 MHz, D2O) δ 2.11−2.22 (m, 1H); 2.45 (dd, J = 17.6 Hz, 6.7 Hz; 1H); 2.76 (dd, J = 17.6 Hz, 9.55 Hz, 1H); 2.90−3.05 (m, 1H); 3.08−3.19 (m, 2H); 3.24−3.36 (m, 1H); 3.43 (dd, J = 9.8 Hz, 5.75 Hz, 1H); 3.49−3.58 (m, 1H); 3.70−3.84 (m, 4H); 3.87 (s, 3H); 3.88 (s, 3H); 4.12 (td, J = 11.6 Hz, 4.5 Hz, 1H); 4.45−4.55 (m, 1H); 4.56−4.68 (m, 3H); 6.91 (s, 1H), 6.95 (s, 1H).
 
 
IR (cm−1): 3237, 2925, 1682, 496, 478.
 
MS (ESI): m/z 378.3 ([M + H]+ (free amine)).
 
Anal. Calcd for C20H30Cl2FN3O3: C, 53.34; H, 6.71; N, 9.33; Cl, 15.74; F 4.22; O, 10.66. Found: C, 53.04; H, 6.43; N, 9.45; Cl, 15.66; F, 4.29; O, 11.09.
REF FOR ABOVE
Mattei, P.; Böhringer, M.; Di Giorgio, P.; Fischer, H.; Hennig, M.; Huwyler, J.; Kocer, B.; Kuhn, B.; Löffler, B. M.; MacDonald, A.; Narquizian, R.; Rauber, E.; Sebokova, E.; Sprecher, U. Bioorg. Med. Chem. Lett. 2010, 20, 1109
Böhringer, M.; Kuhn, B.; Lübbers, T.; Mattei, P.; Narquizian, R.; Wessel,H. P. (F. Hoffmann-La Roche AG). U.S. Pat. Appl. 2004/0259902, 2004.
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Discovery of carmegliptin: A potent and long-acting dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
Bioorg Med Chem Lett 2010, 20(3): 1109
 http://www.sciencedirect.com/science/article/pii/S0960894X09017296
  • Discovery of carmegliptin: A potent and long-acting dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

  • Pages 1109-1113
  • Patrizio Mattei, Markus Boehringer, Patrick Di Giorgio, Holger Fischer, Michael Hennig, Joerg Huwyler, Buelent Koçer, Bernd Kuhn, Bernd M. Loeffler, Alexander MacDonald, Robert Narquizian, Etienne Rauber, Elena Sebokova, Urs Sprecher
  • image
    Full-size image (16 K)
    Scheme 3.

    Reagents and conditions: (a) preparative HPLC (Chiralpak® AD column), heptane/2-propanol 85:15, 37% (b) BH3.Me2S, THF, 0 °C; (c) (MeOCH2CH2)2NSF3, CH2Cl2, 67% (2 steps); (d), SOCl2, ZnCl2, 80 °C, 72 h, 61%; (e) Et3N, CH2Cl2; (f) NaH, DMF, 56% (2 steps); (g) HCl, 1,4-dioxane, 91%; (h) HCl, 2-propanol, 86%.

 The synthesis of 8p is outlined ABOVE and required the enantiopure building blocks (S,S,S)-5 and 12. (S,S,S)-5 was obtained from the racemate by preparative chiral HPLC. Acid chloride 12 was prepared starting from (S)-paraconic acid (9).  Reduction of 9 with borane–dimethyl sulfide complex afforded hydroxymethyl lactone 10. Since 10 is known to racemise rather readily,  it was immediately treated with bis(2-methoxyethyl)aminosulfur trifluoride,  thereby affording fluoromethyl lactone 11. This was converted to 12 by reaction with thionyl chloride in the presence of zinc chloride.  The (S)-4-fluoromethyl-pyrrolidinone 8p was isolated as the dihydrochloride salt, a highly water soluble white crystalline solid, mp >275 °C.
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US 2013109859

The most preferred product is (2S,3S,11bS)-2-tert.-Butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H pyrido[2,1-a]isoquinoline-3-carboxylic acid amide having the following structure:

It has been found that during the amidation of the ester epimerization takes place at position 3 and thus the 3R-epimer of the formula IVb is transformed to a larger extent in the 3S-epimer of formula V.

 

e) Preparation of (2S,3S,11bS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4(S)-fluoromethyl-pyrrolidin-2-one Dihydrochloride

A 2.5 L reactor equipped with a mechanical stirrer, a Pt-100 thermometer, a dropping funnel and a nitrogen inlet was charged with 619 g (1.30 mol) of (2S,3S,11bS)-3-((4S)-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester, 4.2 L isopropanol and 62 mL water and the suspension was heated to 40-45° C. In a second vessel, 1.98 L isopropanol was cooled to 0° C. and 461 mL (6.50 mol) acetyl chloride was added during 35 min, maintaining the temperature at 0-7° C. After completed addition, the mixture was allowed to reach ca. 15° C. and was then slowly added to the first vessel during 1.5 h. After completed addition the mixture was stirred for 18 h at 40-45° C., whereas crystallization started after 1 h. The white suspension was cooled to 20° C. during 2 h, stirred at that temperature for 1.5 h and filtered. The crystals were washed portionwise with 1.1 L isopropanol and dried for 72 h at 45° C./20 mbar, to give 583 g of the product as white crystals (100% yield; assay: 99.0%).

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US 2008071087
Figure US20080071087A1-20080320-C00035
(2S,3S,11bS)-(3-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)]-carbamic acid tert-butyl ester (8)
Example 8
Transformation of (2S,3S,11bS)-(3-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl) ]-carbamic acid tert-butyl ester into (S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl) -4-fluoromethyl-pyrrolidin-2-one.a)
Preparation of 4-fluoromethyl-5H-furan-2-oneA 6 L reactor equipped with a mechanical stirrer, a Pt-100 thermometer, a dropping funnel and a nitrogen inlet was charged with 500 g (4.38 mmol) 4-hydroxymethyl-5H-furan-2-one and 2.0 L dichloromethane. The solution was cooled to −10° C. and 1.12 kg (4.82 mol) bis-(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) was added during 50 min, maintaining the temperature at −5 to −10° C. with a cooling bath. During the addition a yellowish emulsion formed, which dissolved to an orange-red solution after completed addition. This solution was stirred for 1.5 h at 15-20° C., then cooled to −10° C. A solution of 250 ml water in 1.00 L ethanol was added during 30 min, maintaining the temperature between −5 and −10° C., before the mixture was allowed to reach 15-20° C. It was then concentrated in a rotatory evaporator to a volume of ca. 1.6 L at 40° C./600-120 mbar. The residue was dissolved in 2.0 L dichloromethane and washed three times with 4.0 L 1N hydrochloric acid. The combined aqueous layers were extracted three times with 1.4 L dichloromethane. The combined organic layers were evaporated in a rotatory evaporator to give 681 g crude product as a dark brown liquid. This material was distilled over a Vigreux column at 0.1 mbar, the product fractions being collected between 71 and 75° C. (312 g). This material was re-distilled under the same conditions, the fractions being collected between 65 and 73° C., to give 299 g 4-fluoromethyl-5H-furan-2-one (58% yield; assay: 99%).MS: m/e 118 M+, 74,59,41.b) Preparation of (S)-4-fluoromethyl-dihydro-furan-2-oneA 2 L autoclave equipped with a mechanical stirrer was charged with a solution of 96.0 g 4-fluoromethyl-5H-furan-2-one (8.27×10−1 mol) in 284 mL methanol. The autoclave was sealed and pressurized several times with argon (7 bar) in order to remove any traces of oxygen. At ˜1 bar argon, a solution of 82.74 mg Ru(OAc)2((R)-3,5-tBu-MeOBlPHEP) (6.62×10−5 mol) (S/C 12500) in 100 mL methanol was added under stirring from a catalyst addition device previously charged in a glove box (O2 content <2 ppm) and pressurized with argon (7 bar). The argon atmosphere in the autoclave was replaced by hydrogen (5 bar). At this pressure, the reaction mixture was stirred (˜800 rpm) for 20 h at 30° C. and then removed from the autoclave and concentrated in vacuo. The residue was distilled to afford 91.8 g (94%) (S)-4-fluoromethyl-dihydro-furan-2-one. The chemical purity of the product was 99.7% by GC-area.c) Preparation of (2S,3S,11bS)-3-(3-Fluoromethyl-4-hydroxy-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl esterA 1.5 L reactor equipped with a mechanical stirrer, a Pt-100 thermometer, a dropping funnel and a nitrogen inlet was charged with 50 g (128 mmol) (2S,3S,11bS)-3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamic acid tert-butyl ester, 500 mL toluene and 2.51 g (25.6 mmol) 2-hydroxypyridine. To this slightly brownish suspension, 22.7 g (192 mmol) of (S)-4-fluoromethyl-dihydro-furan-2-one was added dropwise at RT. No exothermy was observed during the addition. The dropping funnel was rinsed portionwise with totally 100 mL toluene. The suspension was heated to reflux, whereas it turned into a dear solution starting from 60° C., after 40 min under reflux a suspension formed again. After totally 23 h under reflux, the thick suspension was cooled to RT, diluted with 100 mL dichloromethane and stirred for 30 min at RT. After filtration, the filter cake was washed portionwise with totally 200 mL toluene, then portionwise with totally 100 mL dichloromethane. The filter cake was dried at 50° C./10 mbar for 20 h, to give 60.0 g product (94% yield; assay: 100%).

MS: m/e 496 (M+H)+, 437.

d) Preparation of (2S,3S,11bS)-3-((4S)-Fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl esterA 1.5 L reactor equipped with a mechanical stirrer, a Pt-100 thermometer, a dropping funnel, a cooling bath and a nitrogen inlet was charged with 28 g (56.5 mmol) of (2S,3S,11bS)-3-(3-fluoromethyl-4-hydroxy-butyrylamino) -9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester and 750 mL THF. The mixture was cooled to 0° C. and a solution of 6.17 mL (79 mmol) methanesulfonic acid in 42 mL THF was added during 10 min, maintaining the temperature at 0-5° C. At 0° C. a solution of 12.6 mL (90.2 mmol) triethylamine in 42 mL THF was added during 15 min. The resulting suspension was stirred for 80 min at 0-5° C., whereas it became gradually thicker. Then 141 mL (141 mmol) 1 M lithium-bis(trimethylsilyl)amide were added to the mixture during 15 min, whereas the suspension dissolved. The solution was allowed to reach RT during 60 min under stirring. 500 mL water was added without cooling, the mixture was extracted and the aqueous phase was subsequently extracted with 500 mL and 250 mL dichloromethane. The organic layers were each washed with 300 mL half saturated brine, combined and evaporated on a rotatory evaporator. The resulting foam was dissolved in 155 mL dichloromethane, filtered and again evaporated to give 30.5 g crude product as a slightly brownish foam. This material was dissolved in 122 mL methanol, resulting in a thick suspension, which dissolved on heating to reflux. After 20 min of reflux the solution was allowed to gradually cool to RT during 2 h, whereas crystallization started after 10 min. After 2 h the suspension was cooled to 0° C. for 1 h, followed by −25° C. for 1 h. The crystals were filtered off via a pre-cooled glass sinter funnel, washed portionwise with 78 mL TBME and dried for 18 h at 45° C./20 mbar, to give 21.0 g of the title product as white crystals (77% yield; assay: 99.5%).

MS: m/e 478 (M+H)+, 437, 422.

e) Preparation of (2S,3S,11bS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4(S)-fluoromethyl-pyrrolidin-2-one dihydrochlorideA 2.5 L reactor equipped with a mechanical stirrer, a Pt-100 thermometer, a dropping funnel and a nitrogen inlet was charged with 619 g (1.30 mol) of (2S,3S,11bS)-3-((4S)-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester, 4.2 L isopropanol and 62 mL water and the suspension was heated to 40-45° C. In a second vessel, 1.98 L isopropanol was cooled to 0° C. and 461 mL (6.50 mol) acetyl chloride was added during 35 min, maintaining the temperature at 0-7° C. After completed addition, the mixture was allowed to reach ca. 15° C. and was then slowly added to the first vessel during 1.5 h. After completed addition the mixture was stirred for 18 h at 40-45° C., whereas crystallization started after 1 h. The white suspension was cooled to 20° C. during 2 h, stirred at that temperature for 1.5 h and filtered. The crystals were washed portionwise with 1.1 L isopropanol and dried for 72 h at 45° C./20 mbar, to give 583 g of the product as white crystals (100% yield; assay: 99.0%).

These compounds are useful intermediates for the preparation of DPP-IV inhibitors as disclosed in PCT International Patent Appl. WO 2005/000848. More preferably, the invention relates to a process for the preparation of (2S,3S,11bS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)]-carbamic acid tert-butyl ester.

 

XXXXXXX

According to still another embodiment (Scheme 2, below) the (S)-4-fluoromethyl-dihydro-furan-2-one (VII) is directly coupled with the amino-pyrido[2,1-a]isoquinoline derivative (VI) to form the hydroxymethyl derivative of the pyrido[2,1-a]isoquinoline (VIII), which is then subsequently cyclized to the fluoromethyl-pyrrolidin-2-one derivative (IX). The latter can be deprotected to yield the desired pyrido[2,1-a]isoquinoline derivative (I).

In a further preferable embodiment, the process for the preparation of (S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one or of a pharmaceutically acceptable salt thereof comprises the subsequent steps:

  • e) coupling of the (2S,3S,11bS)-3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamic acid tert-butyl ester (amine of formula VI, wherein R2 and R3 are methoxy, R4 is hydrogen and Prot is Boc) with the (S)-4-fluoromethyl-dihydro-furan-2-one of formula
  • f) cyclization of the obtained (2S,3S,11bS)-3-(3-fluoromethyl-4-hydroxy-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester in the presence of a base, and
  • g) deprotecting the obtained (2S,3S,11bS)-3-((4S)-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester.

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PATENT

 

http://www.google.com.ar/patents/US7122555?cl=pt-PT

 

Example 23

RACEMIC

1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one

a) 4-Fluoromethyl-dihydro-furan-2-one

A solution of 4-hydroxymethyl-dihydro-furan-2-one (Tetrahedron 1994, 50, 6839; 1.02 g, 8.78 mmol) and bis(2-methoxyethyl)aminosulfur trifluoride (3.88 g, 17.6 mmol) in chloroform (4.4 mL) was stirred at 40° C. for 1 h, then poured onto ice and partitioned between sat. aq. sodium hydrogencarbonate solution and dichloromethane. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (576 mg, 56%). Colourless liquid, MS (EI) 118.9 (M+H)+.

b) 3-Chloromethyl-4-fluoro-butyryl chloride

A mixture of 4-fluoromethyl-dihydro-furan-2-one (871 mg, 7.37 mmol), thionyl chloride (4.39 g, 36.9 mmol), and zinc chloride (60 mg, 0.44 mmol) was stirred 72 h at 80° C., then excess thionyl chloride was removed by distillation. Kugelrohr distillation of the residue (85° C., 0.2 mbar) afforded the title compound (450 mg, 35%). Colourless liquid, 1H-NMR (300 MHz, CDCl3): 4.65–4.55 (m, 1H), 4.50–4.40 (m, 1H), 3.70–3.60 (m, 2H), 3.25–3.05 (m, 2H), 2.80–2.60 (m, 1H).

c) (RS,RS,RS)-[3-(3-Chloromethyl-4-fluoro-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester

The title compound was produced in accordance with the general method of Example 5c from (RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamic acid tert-butyl ester (Example 5b) and 3-chloromethyl-4-fluoro-butyryl chloride. White solid, MS (ISP) 514.5 (M+H)+.

d) (RS,RS,RS)-[3-(4-Fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester

The title compound was produced in accordance with the general method of Example 5d from (RS,RS,RS)-[3-(3-chloromethyl-4-fluoro-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester. Off-white foam, MS (ISP) 478.5 (M+H)+.

e) 1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one

The title compound was produced in accordance with the general method of Example 1e from (RS,RS,RS)-[3-(4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester. Light yellow oil, MS (ISP) 378.5 (M+H)+.
Examples 28 and 29

(SR)-1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one

Figure US07122555-20061017-C00040 UNDESIRED

and

 

(RS,RS,RS,RS)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one

The title compounds were produced from 1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one (Example 23) by chromatographic separation (SiO2, CH2Cl2/MeOH/NH4OH 80:1:0.2, then 95:5:0.25).

(SR)-1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one: Yellow oil, Rf=0.45 (CH2Cl2/MeOH/NH4OH 90:10:0.25).

(RS,RS,RS,RS)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one: Light yellow solid, Rf=0.40 (CH2Cl2/MeOH/NH4OH 90:10:0.25).

Example 30

(S)-1-((S,S,S)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one Dihydrochloride

Figure US07122555-20061017-C00042 DESIRED

a) [(S,S,S)-3-(3-Chloromethyl-4-fluoro-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester

The title compound was produced in accordance with the general method of Example 5c from (S,S,S)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamic acid tert-butyl ester (Example 16b) and 3-chloromethyl-4-fluoro-butyryl chloride (Example 23b). Off-white solid.

b) [(S,S,S)-3-((S)-4-Fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester and [(S,S,S)-3-((R)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester

Sodium hydride (55–65% dispersion in oil, 1.14 g, 28.5 mmol) was added to a suspension of [(S,S,S)-3-(3-chloromethyl-4-fluoro-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (6.72 g, 13.1 mmol) in N,N-dimethylformamide (95 mL) at r.t., then after 1 h the reaction mixture was poured onto ice and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, cyclohexane/2-propanol 4:1) afforded [(S,S,S)-3-((S)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (2.40 g, 38%) and the epimer, [(S,S,S)-3-((R)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (2.73 g, 44%).

[(S,S,S)-3-((S)-4-Fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester: Light yellow foam, Rf=0.6 (SiO2, cyclohexane/2-propanol 1:1).

[(S,S,S)-3-((R)-4-Fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester: Light yellow foam, Rf=0.4 (SiO2, cyclohexane/2-propanol 1:1).

    • c) (S)-1-((S,S,S)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one dihydrochloride

[(S,S,S)-3-((S)-4-Fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (2.40 g, 5.02 mmol) was converted to (S)-1-((S,S,S)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one in accordance with the general method of Example 1e. The product was dissolved in 2-propanol (10 mL) and treated with hydrogen chloride (5–6 M in 2-propanol, 37 mL). The suspension formed was stirred for 64 h at r.t., then the precipitate was collected by filtration and dried, to afford the title compound (2.04 g, 91%). White solid, m.p. >300° C.

Example 31(R)-1-((S,S,S)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one dihydrochloride

Figure US07122555-20061017-C00043 UNDESIRED

The title compound was produced in accordance with the general method of Example 30c from [(S,S,S)-3-((R)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (Example 30b). White solid, m.p. >300° C.

 

DR ANTHONY MELVIN CRASTO

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