FIELD OF INVENTION;
The present invention provides an improved process for the synthesis of various
intermediates useful in the synthesis of DPPIV inhibitors, as described in WO 2009/037719
A1.
BACKGROUND OF THE INVENTION:
Dipeptidyl peptidase-IV (DPP-IV) is a membrane bound serine protease, which is widely
expressed in mammalian tissues such as intestine, liver, lung, kidney etc. as a type II integral
membrane protein. The substrate for DPP-IV includes chemokines, neuropeptides, vasoactive
peptides, GLP-1, GLP-2, GHRH and NPY. Recent studies have shown that inhibition of
DPP-IV increases the level of circulating GLP-1 and thus increases the insulin secretion, an
important property in developing therapeutics for the treatment of Type II diabetes. (Ahren,
B et al, Eur. J. Pharmacol. 2000, 404, 239; Paul E. Wiedeman, Progress in Medicinal
Chemistry 2007, 45, 63; Peter Kirkpatrick, Nature Reviews Drug Discovery 2, 92, Feb 2003).
Synthesis of a series of novel and potent DPPIV inhibitor(s) using a key intermediate, methyl
(2S)-2-(tert-butoxycarbonyl)-amino-2-[-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate (compound
of formula n. Scheme 1) is being described in WO 2009/037719 Al and an Indian patent
application Number 880/KOL/2009 dated June 18, 2009. The methodology disclosed in WO
2009/037719 Al, which is described below in scheme 1, employed the use of metal cyanides
under acidic condition as well as Zn powder, in large excess. In addition to the above, the
starting material, 3-hydroxymethyl-8-methyl-8-aza-bicyclo[3.2.1]octan-3-ol (compound of
formula a, Scheme 1) is prepared from tropinone by a four-step conversion involving the use
of sodium cyanide in aqueous hydrochloric acid and Lithium aluminium hydride as well.
Neither these chemicals are safe to handle nor are they eco-friendly on a larger scales.
Further, due to large number of steps involved (17 steps), the overall yield has been found to
be less than 10% and thereby very poor atom economy.
Because of the various reasons mentioned hereinbefore, attempts to prepare methyl (2S)-2-
(tert-butoxycarbonyl)-amino-2-[-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate (compound n) on a
larger scale is not practical and hence an alternative chemistry, which incorporates superior
safety, atom-economy and hazard-free processes needs to be developed. The present

over methanol and tetrahydrofuran (THF) is attributed to the stabilisation of the
intermolecular hydrogen bonded transition state A by the former.

The major isomer in all the above experiments were assigned to be l-(2-hydroxy-1-(1R)-
phenylethyl amino)-1-(8-(benzyloxy carbonyl)-8-aza-bicyclo[3.2.1]-oct-3-yl)-exo-methane-
l-(1S)-carbonitrile (compound 4).
An aspect of the present invention is that the aldehyde 3 could be converted to the
intermediate 4 using other chiral amines such as (R/S) PhCH*(CH3)NH2 or any other chiral
amine which bears an acid labile protection or an orthogonal protection.
Transformation of the l-(2-hydroxy-1-(1R)-phenylethyl amino)-1-(8-(benzyloxy carbonyl)-8-
aza-bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(1S)-carbonitrile (compound 4) to the l-(2-
hydroxy-1-(1R)-phenylethyl amino)-1-(8-(benzyloxy carbonyl)-8-aza-bicyclo[3.2.1]-oct-3-
yl)-exo-methane-1-(1S)-carboxylic acid methyl ester (compound 5) was carried out in
methanolic hydrogen chloride (3M, MeOH-HCl) in a single step. An aspect of the present
invention is that, esters of the type 5 could also be prepared by converting the intermediate 4
to the corresponding acid, followed by esterification using alkyl or aralkyl alcohols. The
above reaction mixture was then subjected to hydrogenolysis using an elevated pressure of
hydrogen over palladium supported on charcoal (Pd/C) at room temperature (rt) or optionally
at 60 °C to give the methyl (25)-2-amino-2-[8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate
hydrochloride (compound 6). Removal of the volatiles followed by treatment of the crude
compound 6 in aqueous saturated sodium bicarbonate solution (satd. aq. NaHCO3) with
benzyl chloroformate (ZC1) at 0 °C, afforded methyl (2S)-2-(benzyloxycarbonyl)-amino-2-[-
8-[benzyloxy carbonyl]-8-azabicyclo[3.2.1]-oct-3-yl]-exo-acetate (compound 7). Compound

7 was subsequently transformed to methyl (2S)-2-((tert-butoxycarbonyl)-[benzyloxy
carbonyl]-amino)-2-[8-(benzyloxy carbonyl)-8-azabicyclo-[3.2.1]oct-3-yl]-exoacetate
(compound 8) by treating with di-tert-butyldicarbonate ((CH3)3COCO)2O) in the presence of
catalytic amount of 4-dimethylaminopyridine (DMAP). Hydrogenation of compound 8 over
palladium supported on charcoal (Pd/C) at an elevated pressure of hydrogen afforded methyl
(2S)-2-(tert-butoxycarbonyl)-amino-2-[-8-azabicyclo(3.2.1)oct-3-yl]-exo-acetate (compound
n).

Alternatively, as shown in the scheme 3, intermediate benzyl 3-(l-formamido-2-ethoxy-2-
oxoethylidene)-8-azabicyclo[3.2.1]-octane-8-carboxylate (compound 9) was prepared by the
condensation of N-protected tropinone (wherein, bridge head N in 1 can be protected either
as amides, ureas or as a urethanes), with an active methylene compounds such as alkyl or aryl
or aralkyl isocyanoacetate in general and methyl or ethyl isocyanoacetate in particular.
Thus, the reaction of compound 1 with ethyl or methyl isocyanoacetate in tetrahydrofuran in
the presence of a base such as sodium hydride (NaH) at 0 °C afforded the dehydro-amino
acid derivative 9. The condensation could also be effected using organic bases such as DBU,

BBN etc. Hydrolysis of the intermediate benzyl 3-(l-formamido-2-ethoxy-2-oxoethylidene)-
8-azabicyclo[3.2.1]-octane-8-carboxylate (compound 9) to a mixture of ethyl or methyl
esters, ie benzyl exo-3-[ethoxy/methoxy(oxo)acetyl]-8-azabicyclo[3.2.1]octane-8-carboxylate
(compound 1O) was carried out by treating 9 with methanolic-HCl (10%). Hydrolysis of 9 to
the keto ester could also be possible using trifluoroacetic acid (TFA), hydrobromic acid
(HBr) in an organic solvent or by using dilute aqueous hydrochloric acid. After evaporation
of the solvents, the residue, benzyl exo-3-[ethoxy/methoxy(oxo)acetyl]-8-
azabicyclo[3.2.1]octane-8-carboxylate (compound 1O) was treated with (S)-(-)-2-methyl-2-
propane sulfinamide in the presence of titanium(IV) ethoxide (Ti(OEt)4), in THF at 60 °C to
give ketimine 10A which was then reduced to l-(S-tert-butylsulfinylamino)-1-(8-(benzyloxy
carbonyl)-8-aza-bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(1S)-carboxylic acid ethyl ester
(compound 11) using various reducing agents such as sodium acetoxy borohydride
((CH3COO)3BHNa), sodium borohydride (NaBH4) or using any modified chiral
borohydrides. The condensation of 10 to 10A could also be effected using dehydrating agents
such as anhydrous copper sulfate or p-toluene sulfonic acid or by using pyridinium p-toluene
sulfonate. Selective reduction of the ketimine 10A generated from 10 to either R or S
intermediate of 11, could also be possible by varylng the use of chiral auxiliary or by
changing the reducing agents such as L-selectride or hydrogenation over chiral catalyst such
as Rhodium complexes or by using metal free catalytic reduction using trichlorosilanes in the
presence of either achiral or chiral ligands as described by Stefania Guizzetti et al, Org. Lett,
2009,11, 2928 and the references herein. Cleavage of sulfinamide protection in 11 followed
by conversion to the requisite intermediate m could be achieved by treating with dilute acids
such as dilute hydrochloric acid (Margaret M. Faul et al, J. Org. Chem. 2006, 71, 6859) or by
treating with methanolic-hydrogen chloride (MeOH-HCl), followed by treating the free
amine with di-tert-butyl dicarbonate ((CH3)3COCO)2O.
The following examples are provided to further illustrate the present invention and therefore
should not be construed to limit the scope of the invention. All 'H NMR spectra were
determined in the solvents indicated and chemical shifts are reported in 5 units downfield
from the internal standard tetramethylsilane (TMS) and inter-proton coupling constants are

reported in Hertz (Hz). The term 'room temperature' means a temperature anywhere between
20°C to 40°C.
Example 1: Synthesis of benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (compound
1).
To a stirred solution of 8-methyl-8-azabicyclo[3.2.1]octan-3-one (200.0 g, 143 mmol) and
K2CO3 (1.19 g) in toluene (4.0 L) was added benzyl chloroformate (1.96 L, 572 mmol, 50%
in toluene) at room temperature and the resulting solution was stirred at reflux for 2 h.
Reaction mixture was cooled to room temperature and then treated with ice-cold water (2.0
L). The organic phase was separated and the aqueous phase extracted with ethyl acetate (2.0
L x 2). Organic phases were combined, dried over anhydrous sodium sulphate, filtered and
evaporated to give a residue, which was purified by vacuum distillation. Yield: 215.0 g
(55%). TLC, Rf (Hexane/Ethyl Acetate 30%) = 0.3. IR cm-1 (CHCl3) 2959, 2887, 1702, 1414,
1367, 1338, 1320, 1284, 1156, 1004, 738. 1HNMR (400 MHz, CDC13): δ 7.32 (m, 5H), 5.19
(s, 2H), 4.59 (br s, 2H), 2.72-2.56 (m, 2H), 2.34 (m, 2H), 2.1 (m, 2H), 1.68 (m, 2H). MS: 258
(M-l).
Example 2: Synthesis of benzyl 8H-spiro[8-azabicyclo[3.2.1]octane-3,2'-oxirane]-8-
carboxylate (compound 2).
To a suspension of sodium hydride (34.5 g, 143 mmol, 50% suspension in hexane) in DMF
(800 mL) was added, a solution of trimethyl sulfonium iodide (118.9 g, 0.58 mol) in DMF
(800 mL), over a period of 1 ½ h.After 15 minutes at room temperature, a solution of benzyl
3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1, 100.0 g, 0.38 mol) in DMF (800 mL) was
added. After stirring for 1 h, the reaction mixture was poured onto ice-cold water (6.4 L) and
then extracted with ethyl acetate (2.0 L x 3). Organic phases were combined, washed with
water (1.0 L x 3), followed by brine (1.0 L) and then dried over anhydrous sodium sulphate.
It was filtered, the filtrate evaporated and the residue was directly used for the next step.
Yield: 105 g. TLC, Rf (Hexane/Ethyl Acetate 30%) = 0.35. IR cm-1(CHCl3) 2950, 1698,
1414, 1322, 1204, 1097, 1008, 760. 'HNMR (400 MHz, CDC13): δ 7.32 (m, 5H), 5.15 (s,
2H), 4.41 (m, 2H), 2.43 (s, 2H), 2.38 (m, 2H), 2.13-1.99 (m, 4H), 1.22 (m, 2H). MS: 274
(M+l)+.

Example 3: Synthesis of benzyl 3-exo-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate
(compound 3).
To a stirred solution of benzyl 8H-spiro[8-azabicyclo[3.2.1]octane-3,2'-oxirane]-8-
carboxylate (2, 100.0 g, 0.36 mol) in dichloromethane (1.2 L) at room temperature, was
added BF3-etherate (26.0 g, 0.18 mol), drop wise, over a period of ½ h. Stirring was
continued for 2 h and the reaction mixture was treated with ice-cold water (500 mL). Organic
phase was separated and washed with saturated sodium bicarbonate solution (500 mL),
followed by brine (500 mL). It was dried over anhydrous sodium sulphate, filtered and
concentrated under vacuo to give a residue, which was purified over silica gel column using a
gradient of ethyl acetate in hexane. Yield: 70.6 g (71%). TLC, Rf (Hexane/Ethyl Acetate
30%) = 0.3. IR cm-1 (CHC13) 2954, 1698, 1422, 1328, 1213, 1102, 1078, 751. 1HNMR (400
MHz, CDCl3): δ 9.54 (s, 1H), 7.33 (m, 5H), 5.14 (s, 2H), 4.39 (m, 2H), 2.82 (m, 1H), 2.06 -
1.65 (m, 8H). MS:274(M+1)+.
Example 4: Synthesis of 1-(2-hydroxy-1-(1R)-phenylethyl amino)-1-(8-(benzyloxy
carbonyl)-8-aza-bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(1S)-carbonitrile (compound 4).
To a stirred solution of benzyl 3-exo-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate (3,
98.0 g, 0.35 mol) in methanol (686 mL) under nitrogen, was added R-(-)-2-phenyl glycinol
(49.2 g, 0.35 mol) followed by glacial acetic acid (22 mL), drop wise, over a period of 5 min.
After ½ h at room temperature, trimethylsilyl cyanide (39.1 g, 0.39 mol) was added
dropwise. Stirring was continued for an additional 2 h and the reaction quenched by treating
with DM water (686.0 mL). Volatiles were removed under vacuum and the residue extracted
with ethyl acetate (1.5 L x 2). Organic phases were combined and the combined extract
washed with DM water (1.0 L) followed by brine (1.0 L) and then dried over anhydrous
sodium sulphate. It was filtered, concentrated in vacuo and the residue was dissolved in
methanolic hydrogen chloride (4M, 300 mL). Into this was added diethyl ether (500 mL) and
the mixture kept at room temperature overnight. The white solid separated was filtered,
washed with diethyl ether and dried. Yield = 63.0 g (42%). TLC, Rf (Hexane/Ethyl Acetate
40%) = 0.4. IR cm-1 (CHCl3) 3248, 2951, 1686, 1454, 1425, 1326, 1212, 1103, 757. 1HNMR
(400 MHz, CDCl3): δ 7.33 (m, 10H), 5.13 (s, 2H), 4.36 (m, 2H), 4.07 (dd, J= 3.6, 9.2 Hz,

1H), 3.77 (dd. J= 3.6, 10.8, 1H), 3.53 (t, J= 10Hz, 1H), 3.02 (br s, 1H), 2.17 (br m, 1H),
2.05-1.80 (m,4H), 1.74-1.41 (m, 4H). MS: 420 (M+l)+.
Example 5: Synthesis of l-(2-hydroxy-1-(1R)-phenylethyl amino)-l-(8-(benzyloxy
carbonyl)-8-aza-bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(1S)-carboxylic acid methyl ester
hydrochloride salt (compound 5).
To a stirred solution of l-(2-hydroxy-1-(1R)-phenylethyl amino)-1-(8-(benzyloxy carbonyl)-
8-aza-bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(1S)-carbonitrile (4, 45.0 g, 0.107 mol) in
methanol (540 mL), at room temperature, was purged dry hydrogen chloride gas until the
molarity of the solution become 3. It was kept at room temperature for 24 h and then
concentrated to give a semi solid, which was sufficiently pure for the next step. IR cm-1
(CHC13) 3320, 2923, 1698, 1533, 1420, 1327, 1101, 784. 1HNMR (400 MHz, CDC13): δ 7.30
(m, 10 H), 5.12 (s, 2H), 4.30 (m, 3H), 3.69 (s, 3H), 3.60 (m, 2H), 2.83 (d, J =1.2 Hz, 1H),
1.5-2.1 (m, 8H). MS: 453 (M+l)+.
Example 6: Synthesis of methyl (2S)-2-amino-2-[8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate,
hydrochloride salt (compound 6).
A solution of l-(2-hydroxy-1-(1R)-phenylethyl amino)-1-(8-(benzyloxy carbonyl)-8-aza-
bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(1S)-carboxylic acid methyl ester hydrochloride salt
(5, 45.0 g, 90 mmol) in methanolic-hydrogen chloride (450 mL, 1M), was hydrogenated over
palladium supported on charcoal (20%, 22.5 g) using a positive pressure of hydrogen (20 Kg)
at 60 °C for 12 h. It was then filtered through a celite pad and washed with methanol (250
mL). The filtrate was concentrated in vacuo to give a pale yellow semi solid, which was used
for the next step without further purification. 1HNMR (400 MHz, DMSO-d6): δ 9.34 (s, 1H),
8.81 (s, 2H), 3.96 (br s, 2H), 3.76 (s, 3H), 1.97-1.83 (m, 3H), 1.20-1.10 (m, 6 H). MS: 199
(M+l)+.
Example 7: Synthesis of methyl (2S)-2-(benzyloxycarbonyl)-amino-2-[-8-[benzyloxy
carbonyl]-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate (compound 7).
Methyl (2S)-2-amino-2-[8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate, hydrochloride salt (6, 23.0
g, 80 mmol) was dissolved in a mixture of DM water and 1,4 dioxane (230 mL, 1:1). The
resulting solution was then cooled to 0 °C and was treated with aqueous saturated sodium

bicarbonate till the pH of the solution become 7.5. Into this was added benzyl chloroformate
(42.19 g, 0.24 mol, 50% in toluene), drop wise, such that pH remains around 7.5. It was
stirred for 3 h at 0 °C and then extracted with ethyl acetate (500 raL x 3). Organic phases
were combined and the combined phase was washed with DM water (500 mL) followed by
brine (500 mL) and then dried over anhydrous sodium sulphate. It was filtered, concentrated
in vacuo and the residue was purified over silica gel column using a gradient of ethyl acetate
in hexanes to give colourless oil. Yield = 21.2 g (55%). TLC, Rf (Hexane/Ethyl Acetate 40%)
= 0.3. 1HNMR (400 MHz, CDC13): δ 7.34 (m, 10 H), 5.29 (m, 1H), 5.12 (s, 2H), 5.03 (s, 2H),
4.26 (m, 3H). 3.71 (s. 3H), 2.33 (m, 1H), 1.96 (m, 2H), 1.64-1.25 (m, 6H). MS: 467 (M+l)+.
Example 8: Synthesis of methyl (2S)-2-((tert-butoxycarbonyl)-[benzyloxy carbonyl]-
amino)-2-[8-(benzyloxy carbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate (compound 8).
To a stirred solution of methyl (2S)-2-(benzyloxycarbonyl)-amino-2-[-8-[benzyloxy
carbonyl]-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate (7, 21.0 g, 40 mmol) and DMAP (1.09 g ,
9 mmol) in acetonitrile (210 mL) was added di-tert-butyl dicarbonate (23.57 g, 108 mmol) at
room temperature. It was stirred for 12 h and then treated with DM water (420 mL) and
extracted with ethyl acetate (0.5 L x 2). Organic phases were combined; combined phase was
washed with DM water (250 mL x 2), followed by brine (0.25 L x 2) and then dried over
anhydrous sodium sulfate. It was filtered and concentrated in vacuo. The residue thus
obtained was purified over silica gel column using a gradient of ethyl acetate in hexanes to
give pale yellow colored oil. Yield = 24.3 g (76%). TLC, Rf (Hexane/Ethyl Acetate 40%) =
0.4. IR cm-1 (CHC13) 2976, 1750, 1701, 1395, 1233, 1151, 1105, 753. 1HNMR (400 MHz,
CDCl3): δ 7.34 (m, 10H), 5.26 (m, 2H), 5.13 (s, 2H), 4.61 (d, .7=9.2 Hz, 1H), 4.30 (m, 2H),
3.64 (s, 3H), 2.75 (m, 1H), 2.17 (m, 1H), 1.91 (m, 2H), 1.71 (m, 1H), 1.58-1.33 (m, 5H). MS:
467 (M-99)+, 589 (M+Na)+.
Example 9: Synthesis of methyl (2S)-2-(tert-butoxycarbonyl)-amino-2-[-8-
azabicyclo[3.2.1]oct-3-yl]-exo-acetate (compound n).
A solution of methyl (2S)-2-((tert-butoxycarbonyl)-[benzyloxy carbonyl]-amino)-2-[8-
(benzyloxy carbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate (8, 3.5 g, 6.1 mmol) was
hydrogenated over palladium supported on charcoal (10%, 0.35 g) using a positive pressure
of hydrogen (5 Kg) at room temperature for 2 h. It was the filtered through a celite pad and

the filtrate was concentrated to dryness. Yield: 1.50 g (89%). IR cm-1 (CHC13) 3445, 1644,
1519, 1367, 116. 754. 1HNMR (400 MHz, CDC13+D2O): δ 4.19 (d, J=9.6 Hz, 1H), 3.72 (s,
3H), 3.56 (brs, 2H), 2.10-2.22 (m, 1H), 1.70-1.85 (m, 2H), 1.52-1.68 (m, 2H), 1.30-1.50 (m.
13H). MS: 299 (M+l)+. [α]D20: -3.74 (c=l, MeOH)
Example 10: Synthesis of l-(2-hydroxy-1-(1R)-phenylethyl amino)-1-(8-(benzyloxy
carbonyl)-8-aza-bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(1S)-carbonitrile (compound 4).
To a stirred solution of benzyl 3-exo-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate (3, 50
mg, 0.18 mmol) in dichloromethane (3.5 mL) under nitrogen at ambient temperature, was
added R-(-) -2-phenyl glycinol (30 mg, 0.22 mmol) followed by glacial acetic acid (0.1 mL).
After l/2 h at room temperature, trimethylsilyl cyanide (20 mg, 0.22 mmol) was added and
stirring continued for 2 h. The reaction was quenched by treating with DM water (3.0 mL)
and evaporated under vacuum. The residue was extracted with ethyl acetate (3.0 mL x 2),
washed with DM water (3.0 mL) followed by brine (3.0 mL) and then dried over anhydrous
sodium sulfate. It was filtered, concentrated and the residue analyzed by reverse phase HPLC.


Method and analysis: Analytical reversed-phase HPLC was performed on a Supelco C-18
column (50 x 4.6 mm, 2.7 u), eluted with a gradient of acetonitrile (MeCN) in water
(containing 20 mM KH2PO4, pH=3.O), flow rate 0.7 mL/min, detection at 210 nm.
Example 1.1: Synthesis of benzyl 3-(l-formamido-2-ethoxy-2-oxoethylidene)-8-
azabicyclo[3.2.1]-octane-8-carboxylate (compound 9).
To a stirred solution of sodium hydride (47.0 g, 1.59 mol) in tetrahydrofuran (5.0 L) was
added a solution of ethyl isocyanoacetate (192 g, 1.41 mol) in tetrahydrofuran (1.2 L), drop
wise, over a period of 30 min at 0-10 °C. After 45 minutes at this temperature, a solution of
benzyl 3-oxo-8-azabicyclo[3.2.1]-octane-8-carboxylate (1, 335 g, 1.08 mol), in
tetrahydrofuran (1.25 L) was added dropwise over a period of 30 min. It was stirred for 1 h at

0-10 °C and the reaction quenched by treating with crushed ice. Reaction mass extracted with
ethyl acetate (2x5L), organic phases combined and the combined organic phase washed with
brine (5L). It was dried over anhydrous sodium sulfate, filtered and concentrated under
vacuum. The residue was re-crystallized from ethyl acetate/Hexane to give a colorless solid.
Yield: 345 g (76%). MP: 124.5 °C. IR cm-1 (CHC13) 3288, 989, 1705, 1506, 1422, 1311,
1203, 1092, 1036, 754. 1HNMR (400 MHz, CDC13) δ: 8.17 (s, 1H), 7.37 (br s, 5H), 5.19 (s,
2H), 4.40 (br s, 2H), 4.20 (q, 2H, J= 7.14 Hz), 2.31 (m, 3H), 1.70 (m, 3H), 1.50 (m. 2H),
1.29 (t, 3H, J= 7.14Hz). MS: 373 (M+l)\ 390 (M+H2O)+, 395 (M+Na)+
Example 12: Synthesis of benzyl exo-3-[ethoxy/methoxy(oxo)acetyl]-8-azabicyclo-
[3.2.1]octane-8-carboxylate (compound 10).
To a solution of benzyl 3-(l-formamido-2-ethoxy-2-oxoethylidene)-8-azabicyclo[3.2.1]-
octane-8-carboxylate (9, 100 g, 0.27 mol) in methanol (1L) at 0 °C, was added methanolic-
hydrogen chloride (200 mL, 4M) and the solution stirred for 12 h. It was concentrated and
the residue dissolved in ethyl acetate (1.0 L) and dried over anhydrous sodium sulfate. It was
filtered and concentrated. The residue re-dissolved in dichloromethane (2.0 L) and treated
with charcoal (30 g). It was filtered and concentrated. The residue, which contains a mixture
of ethyl amd methyl ester, used as such for the next step without further purification. Yield:
82.0 g (92%). IR cm-1 (CHCl3) 3423, 1644, 1417, 1096, 770. 1HNMR (400 MHz, CDCl3) 8:
7.34 (s, 5H), 5.18 (s, 2H), 4.40 (brs, 2H), 4.20-4.50 (m, 3H), 3.85 (s, 2H), 3.55 (m, 1H), 1.62-
2.00 (m, 8H), 1.28 (m, 2H). MS: 330 (M-l).
Example 13: Synthesis of Benzyl 3-[(1E/Z)-N-((S)-tert-butylsulfinyl)-2-ethoxy-2-
oxoethanimidoyl]-8-azabicyclo[3.2.1 ]octane-8-carboxylate (compound 10A).
To a stirred solution of mixture of benzyl exo-3-[ethoxy or methoxy(oxo)acetyl]-8-
azabicyclo[3.2.1]octane-8-carboxylate (10, 20.0 g, 0.06 mol) in tetrahydrofuran (600 mL)
was added S-(-)-tert-butyl sulfinamide (9.54 g, 0.078 mol) followed by Ti(OEt)4 (27.63 g,
0.12 mol) and the resulting solution was refluxed for 12h during which tlc showed the
disappearance of 10. It was diluted with a mixture of ethyl acetate:water (2:1, 1.8 L), filtered
through celite bed. Layers were separated and dried over anhydrous sodium sulfate. It was
filtered and the filtrate concentrated. The residue re-dissolved in dichloromethane (500 mL)

invention provides a solution for most of the problems existing in the reported method for the
synthesis of compound of formula n and its penultimate compound of formula m.

SUMMARY OF INVENTION:
The present invention relates to an improved process for the preparation of a key
intermediate viz. methyl (2S)-2-(tert-butoxycarbonyl)-amino-2-[-8-azabicyclo[3.2.1]oct-3-
yl]-exo-acetate (compound of formula n) useful for the preparation of DPP-IV inhibitors, as
schematically provided in 'Scheme - A'.
Scheme A illustrates, various approaches towards the syntheses of compound of the formula
n and its analogues. In addition to our recently reported synthesis (WO 2009/037719 Al) of
intermediate n, which employed 17 steps (Scheme 1), the present strategies outlined in
scheme 2 and 3 offers more practical, cost effective, safe and eco-friendly process routes.
While scheme 2 leads to the intermediate n in 8 steps, scheme 3 offers n in 6 steps.

and treated with charcoal (20 g) at 40 °C. It was filtered through celite pad and the filtrate
treated with neutral alumina (40g) for a period of 45 min. Solids was filtered, washed with
dichloromethane and the filtrate evaporated. Yield: 19.2 g (70%). MP: 99.4 °C. IR cm-1
(KBr) 2976, 1738, 1706, 1624, 1452, 1404, 1258, 1079, 975, 870, 743. 1HNMR (400 MHz,
CDC13) 5: 7.31 (5H, brs), 5.17 (s, 2H), 4.20-4.50 (m, 4H), 3.08 (m, 1H), 2.02 (m, 3H), 1.54
(m, 6H). 1.35 (t,./ = 6.3 Hz, 3H), 1.22 (s, 9H). MS: 449 (M+l)+.
Example 14: Synthesis of l-(S-tert-butylsulfmylamino)-1-(8-(benzyloxy earbonyl)-8-aza-
bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(lS)-carboxylic acid ethyl ester (compound 11).
To a solution of benzyl 3-[(l£'/Z)-N-((S)-tert-butylsulfinyl)-2-ethoxy-2-oxoethanimidoyl]-8-
azabicyclo[3.2.1]octane-8-carboxylate (10A, 5.0 g, 11.5 mmol) in tetrahydrofuran (50 mL) at
room temperature was added triacetoxy borohydride (14.61 g, 67 mmol) and mixture stirred
for 24 h. Reaction quenched by treating with methanol (25 mL) followed by water (50 mL)
and extracted with ethyl acetate (3x50 mL). Organic phases combined, washed with water
followed by brine and then dried over anhydrous sodium sulfate. It was filtered and the
filtrate concentrated to dryness. The residue thus obtained was used directly for the next step.
Yield: δ.30 g. IR cm-1 (KBr) 3462, 3235, 2957, 1739, 1682, 1447, 1417, 1331, 1263, 1102,
1070, 1027, 893, 764, 735. 1HNMR (400 MHz, CDC13) δ: 7.33 (brs, 5H), 5.12 (s, 2H), 4.35
(brs, 2H), 4.13 (m, 2H), 3.66 (2H, m), 2.23 (m, 1H), 1.96 (brs, 2H), 1.63 (brs, 6H), 1.25 (m,
3H), 1.18 (s, 9 H). MS: 451 (M+l)+.
Example 15: Synthesis of ethyl (2S)-2-((tert-butoxycarbonyl)-amino)-2-[8-(benzyloxy
carbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate (compound m).
A solution of l-(S-tert-butylsulfinylamino)-1-(8-(benzyloxy carbonyl)-8-aza-bicyclo[3.2.1]-
oct-3-yl)-exo-methane-1-(lS)-carboxylic acid ethyl ester (compound 11, 5.3 g, crude) in
methanol (50 mL) was added methanolic-hydrogen chloride (10 mL, 3M) and the resulting
solution stirred at room temperature for 3 h during which tlc showed the disappearance of the
starting material. It was concentrated and dried. It was dissolved in tetrahydrofuran (74 mL)
and treated with triethylamine till the pH of the solution was neutral. Into this was added di-
tert-butyl dicarbonate (2.95 g) and the reaction mixture stirred for 12 h. Reaction was
quenched by adding water (74 mL) and extracted with dichloromethane (3 x 75 mL). Organic

phases combined, washed with water and dried over anhydrous sodium sulfate. It was filtered
and the filtrate evaporated to dryness. The residue was purified over silica gel column using a
gradient of ethyl acetate in petroleum ether to give m as gummy solid. Yield: 4.0 g (82%). IR
cm-1 (KBr) 3337, 2972, 2927, 1702, 1526, 1457, 1333, 1171, 1098, 1020, 864, 755. 754.
1HNMR (400 MHz. CDC13) 5: 7.35 (brs, 5H), 5.13 (s, 2H), 5.00 (m, 1H), 4.35 (m, 2H), 4.18
(m, 2H). 2.32 (m, 1H), 1.96 (m, 2H), 1.52-1.73 (m, 6H), 1.45 (s, 9H), 1.26 (/, ./ = 7.2 Hz,
3H). MS: 348 (M-Boc)+, 447 (M+l)+.


As mentioned hereinabove the present invention provides an alternative improved processes
for the synthesis of methyl (2S)-2-(tert-butoxycarbonyl)-amino-2-[-8-azabicyclo[3.2.1]oct-3-
yl]-exo-acetate (compound of formula n) comprising:
• Sequence as depicted in scheme 2.

• Sequence as depicted in scheme 3.
Scheme 2:
(i) conversion of benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (compound
1) to benzyl 3-exo-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate (compound 3)
using a two-step procedure employing trimethylsulfonium iodide ((CH3)3S+I) and
boron trifluoride-diethyl etherate (BF3-etherate) in dichloro methane (DCM).

(ii) conversion of benzyl 3-exo-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate
(compound 3) to l-(2-hydroxy-l-(1R)-phenylethyl amino)-1-(8-(benzyloxy
carbonyl)-8-aza-bicyclo[3.2.1]-oct-3-yl)-exo-methane-l-(1S)-carbonitrile
(compound 4) following the Strecker synthesis using R-(-)-2-Phenyl glycinol as
the chiral auxiliary and Trimethylsilyl cyanide (TMSCN) as the cyanide source,
and the reaction can be carried out in either alcoholic or chlorinated solvents in
general, methanol (MeOH) or dichloromethane (DCM) or chlroform (CHCl3) in
particular in the presence of acetic acid (AcOH) or any other Lewis acid.

(iii) hydrolysis of the nitrile group in l-(2-hydroxy-l-(1R)-phenylethyl amino)-1-(8-
(benzyloxy carbonyl)-8-aza-bicyclo[3.2.1]-oct-3-yl)-exo-methane-l-(lS)-
carbonitrile (compound 4) using methanolic-hydrogen chloride (MeOH-HCl) to
obtain l-(2-hydroxy-l-(1R)-phenylethyl amino)-1-(8-(benzyloxy carbonyl)-8-aza-
bicyclo-[3.2.1]-oct-3-yl)-exo-methane-l-(1S)-carboxylic acid methyl ester
hydrochloride (compound 5).


(iv) conversion of l-(2-hydroxy-1-(1R)-phenylethyl amino)-1-(8-(benzyloxy
carbonyl) -8-aza-bicyclo[3.2. l]-oct-3-yl)-exo-methane-1-(1S)-carboxylic acid
methyl ester (compound 5) to methyl (2S)-2-amino-2-[8-azabicyclo[3.2.1]oct-3-
yl]-exo-acetate hydrochloride (compound 6) by the de-protection of amino group
using an elevated pressure of hydrogen over palladium supported on charcoal
(Pd/C).

(v) protection of the amino groups in methyl (2S)-2-amino-2-[8-azabicyclo-
[3.2.1]oct-3-yl]-exo-acetate hydrochloride (compound 6) using benzyl
chloroformate (ZC1) in the presence of aqueous saturated sodium bicarbonate
solution (aq. NaHCO3) to give methyl (2S)-2-(benzyloxycarbonyl)-amino-2-[-8-
[benzyloxy carbonyl]-8-azabicyclo-[3.2.1]oct-3-yl]-exo-acetate (compound 7).

(vi) conversion of methyl (2S)-2-(benzyloxycarbonyl)-amino-2-[-8-[benzyloxy
carbonyl]-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate (compound 7) to methyl (2S)-
2-((tert-butoxycarbonyl)-[benzyloxy carbonyl]-amino)-2-[8-(benzyloxy carbonyl)
-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate (compound 8) using di-tert-butyl
dicarbonate ((CH3)3COCO)2O and 4-dimethylaminopyridine (DMAP) in an
aprotic organic solvent such as acetonitrile (ACN).


(vii) hydrogenolysis of methyl (2S)2-((tert-butoxycarbonyl)-[benzyloxy carbonyl]-
amino)-2-[8-(benzyloxy carbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate
(compound 8) over palladium supported on charcoal (Pd/C) to give methyl (2S)-2-
(tert-butoxycarbonyl)-amino-2-[-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate
(compound n).

Another aspect of the present invention is to provide an improved process as shown in
scheme 3, vide infra, for the synthesis of compound of formula m, a penultimate intermediate
in the synthesis of compound of the formula n comprising of
i. conversion of benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (compound 1) to
benzyl 3-(l-formamido-2-ethoxy-2-(oxo)ethylidene)-8-azabicyclo[3.2.1]-octane-8-
carboxylate (compound 9) by the condensation of compound of formula 1 with an
active methylene compounds such as methyl or ethyl isocyanoacetate in the presence
of sodium hydride (NaH) in an aprotic solvent such as tetrahydrofuran (THF) or in
1,4-dioxane or any water miscible cyclic ether.


ii. conversion of compound of formula 9 to a mixture of benzyl exo-3-[efhoxy or
methoxy (oxo)acetyl]-8-azabicyclo[3.2.1]octane-8-carboxylate (compound 1O) by
treatment with methanolic hydrogen chloride (MeOH-HCl).

iii. conversion of compound of formula 10 to 1-((either S or R)-/err-butylsulfinylamino)-
1 -(8-(benzyloxy carbonyl)-8-aza-bicyclo[3.2. l]-oct-3-yl)-exo-methane-l -(1S)-
carboxylic acid ethyl ester (compound 11) by first treating compound 10 with either
(S)(-)-2-methyl-2-propane sulfinamide or with (R)-(+)- 2-methyl-2-propane
sulfanamide in the presence of titanium(IV) ethoxide (Ti(OEt)4 and followed by further
reduction of the intermediate ketimine 10A, using a suitable reducing agent such as
sodium borohydride (NaBH4) or sodium triacetoxy borohydride ((CH3COO)3BHNa)
or any other reducing agents.

iv. conversion of compound of formula 11 to compound m first by treatment with
methanolic-hydrogen chloride (MeOH-HCl), followed by treatment with di-tert-butyl
dicarbonate ((CH3)3COCO)2O. Further m can be converted to n by the known process.


Such that at each step the intermediates were optionally isolated and purified with suitable
process.
It is to be emphasized that the schemes 2 and 3 starting compound is compound of formula 1
and ends up in n only the difference is the "in between".
Compound of formula n can be further converted to DPP-IV inhibitors as described in WO
2009/037719 and an Indian patent application Number 880/KOL/2009 dated June 18, 2009.
DETAILED DESCRIPTION OF THE INVENTION:
In the present invention, new compounds and their synthesis are provided, for the production
of inhibitors as described in our pending application PCT WO 2009/037719 Al.
As shown in scheme 2, the key intermediate, benzyl 3-exo-formyl-8-azabicyclo[3.2.1]octane-
8-carboxylate (compound 3) was obtained from benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-
carboxylate (compound 1) using Corey-Chaykovsky reaction (Corey, E.J et al, J. Am.
Chem.Soc, 1962, 84, 867-868) to give benzyl 8H-spiro[8-azabicyclo[3.2.1]octane-3,2'-
oxirane]-8-carboxylate (compound 2), followed by epoxide opening using boron trifluoride-
diethyl etherate (BFj-etherate). In this reaction, a solution of benzyl 3-oxo-8-azabicyclo
[3.2.1]octane-8-carboxylate (compound 1) in dimethyl formamide (DMF) was added to a
solution of dimethylsulfonium ylide generated in situ by treating trimethylsulfonium iodide
((CH3)3S+I) with sodium hydride (NaH) in dimethyl formamide (DMF). The reaction was
carried out at room temperature and generally complete within an hour. The reaction mixture
was then poured onto crushed ice and then extracted with ethyl acetate. Subsequently, the
organic phase was washed with water followed by brine solution and then concentrated. The
epoxide, benzyl 8H-spiro[8-azabicyclo[3.2.1]octane-3,2'-oxirane]-8-carboxylate (compound
2) was then opened to a mixture of exo and endo aldehydes, benzyl 3-formyl-8-
azabicyclo[3.2.1]octane-8-carboxylate (compound 3) by using boron trifluoride-diethyl
etherate (BF3-etherate) in dichloromethane (DCM), employlng Meinwald rearrangement
(Meinwald J et al J. Am. Chem. Soc 1963, 85, 582-585) and the more thermodynamically
stable exo aldehyde was obtained either by distillation or by column chromatography over
silica gel or by treating with an appropriate base such as DBU.


As shown in scheme 2, the exo-aldehyde, benzyl 3-exo-formyl-8-azabicyclo[3.2.1]octane-8-
carboxylate (compound 3) in chloroform (or in methanol) was treated with chiral auxiliary
namely, R-(-)-2-phenyl glycinol in the presence of acetic acid (AcOH) and the intermediate
Schiff base formed in situ was treated with trimethyl silylcyanide (TMSCN) to give
diasteromeric mixture of 1-(2-hydroxy-1-(1R)-phenylethyl amino)-1-(8-(benzyloxy
carbonyl)-8-aza-bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(1S or 1R)-carbonitrile (4) (79:21;
15,l'R; 1R,1'R). The diasteromeric mixture could be further separated either using column
chromatography or by forming salts in general and hydrochloride salt in particular by treating
the mixture with methanolic-hydrogen chloride (MeOH-HCl). The less soluble 1 -(2-hydroxy-
l-(1R)-phenylethyl amino)-1-(8-(benzyloxy carbonyl)-8-aza-bicyclo[3.2.1]-oct-3-yl)-exo-
methane-1-(1S)-carbonitrile (4) crystallized as an off white solid.
Further improvement in diastereo selectivity was explored using different solvents and
temperature as tabulated in Table 1. As shown in the table 1, the best selectivity was obtained
by using chlorinated solvents in general and dichloro methane (DCM) in particular at room
temperature (rt) (example 10). The enhanced diastereo selectivity by the chlorinated solvents

We claim:
1. A process for the synthesis of compound of formula n

wherein, R1 is selected from C1 to C4 alkyl or benzyl; comprising:
(i) conversion of compound of formula 1 to compound of formula 3 by first
converting compound of formula 1 to an oxiranyl compound 2 by treatment with
sodium hydride and trimethylsulfonium iodide in N,N-dimethylformamide at
temperature between 20 to 40 °C and further to compound of formula 3 by
treatment with BF3-etherate in dichloromethane at room temperature;

Wherein, R is selected from C1 to C4 alkyl, substituted or unsubstituted benzyl,
substituted or unsubstituted phenyl, C1 to C4 alkyloxy, substituted or
unsubstituted benzyloxy, C1 to C6 alkylamino, C1 to C6 dialkylamino;
(ii) conversion of compound of formula 3 to compound of formula 4 following the
Strecker synthesis using chiral amine such as R-(-)-2-Phenyl glycinol or R-(-)-2-
phenylethylamine or their optical isomers as a chiral auxiliary and TMSCN as a
cyanide source in an organic solvent selected from dichloromethane, methanol,
chloroform, 1,2-ethylenedichloride, hexane, tetrahydrofuran,
methyltetrahydrofuran, DME or mixtures thereof in the presence of acetic acid, or
Lewis acid at a temperature between -40 and 25 °C;


Wherein, R is selected from C1 to C4 alkyl, substituted or unsubstituted benzyl,
substituted or unsubstituted phenyl, C1 to C4 alkyloxy. substituted or
unsubstituted benzyloxy, C1 to C6 alkylamino, C1 to C6 dialkylamino; and R2 is
selected from (R/S) -C*H(Ph)CH2OH, (R/S) -C*H(Ph)CH3, wherein, asterisk denotes
point of attachment;
(iii) hydrolysis of the nitrile group in compound of formula 4 using alcoholic-HCl to
obtain compound of formula 5 at room temperature;

Wherein, R is selected from C1 to C4 alkyl, substituted or unsubstituted benzyl,
substituted or unsubstituted phenyl, C1 to C4 alkyloxy, substituted or
unsubstituted benzyloxy, C1 to C6 alkylamino, C1 to C6 dialkylamino; Rl is
selected from C1 to C4 alkyl or benzyl; and R2 is selected from (R/S) -
C*H(Ph)CH2OH, (R/S) -C*H(Ph)CH3 wherein, asterisk denotes point of attachment;
(iv) conversion of compound of formula 5 to compound of formula 6 by the de-
protection of amino group in the presence of palladium supported on charcoal
(Pd/C) at around 20 Kg pressure of hydrogen at a temperature of about 60 °C in
mefhanolic-HCl;


Wherein, R is selected from C1 to C4 alkyl, substituted or unsubstituted benzyl,
substituted or unsubstituted phenyl, C1 to C4 alkyloxy, substituted or
unsubstituted benzyloxy, C1 to C6 alkylamino, C1 to C6 dialkylamino; Rl is
selected from C1 to C4 alkyl or benzyl; and R2 is selected from (R/S) -
C*H(Ph)CH2OH, (R/S) -C*H(Ph)CH3 wherein, asterisk denotes point of attachment;
(v) reaction of compound of formula 6 with benzyl chloroformate in the presence of
aqueous saturated sodium bicarbonate solution in aqueous 1,4-dioxane at around
0°C to give compound of formula 7;

Wherein, Rl is selected from C1 to C4 alkyl or benzyl;
(vi) conversion of compound of formula 7 to compound of formula 8 using di-terl-
butyl dicarbonate and 4-dimethylaminopyridine in an aprotic organic solvent such
as acetonitrile at room temperature;

wherein, Rl is selected from C1 to C4 alkyl or benzyl;
(vii) hydrogenolysis of compound of formula 8 over palladium supported on charcoal
(Pd/C) at around 5 Kg pressure of hydrogen at room temperature to give
compound of formula n;


wherein. Rl is selected from C1 to C4 alkyl or benzyl;
such that
at each step the product is optionally isolated and purified by techniques such as crystallization,
column chromatography or distillation.
2. A process for the synthesis of methyl (2S)-2-(tert-butoxycarbonyl)-ammo-2-[-8-
azabicyclo[3.2.1]oct-3-yl]-exoacetate comprising of hydrogenolysis of methyl (2S)-2-((tert-
butoxycarbonyl)-[benzyloxy carbonyl]-amino)-2-[8-(benzyloxy carbonyl)-8-azabicyclo
[3.2.1]oct-3-yl]-exo-acetate in presence of palladium supported on charcoal at around 5 Kg
pressure of hydrogen at room temperature followed by isolation of the product formed.
3. The process as claimed in claim 2, wherein methyl (2S)-2-((tert-butoxycarbonyl)-[benzyloxy
carbonyl]-amino)-2-[8-(benzyloxy carbonyl)-8-azabicyclo [3.2.1]oct-3-yl]-exo-acetate is
synthesized by reaction of methyl (2S)-2-(benzyloxycarbonyl)-amino-2-[-8-[benzyloxy
carbonyl]-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate with di-tert-butyl dicarbonate and 4-
dimethylamino pyridine in an aprotic organic solvent such as acetonitrile at room
temperature followed by optional isolation and purification of methyl (2S)-2-((tert-
butoxycarbonyl)-[benzyloxy carbonyl]-amino)-2-[8-(benzyloxy carbonyl)-8-azabicyclo
[3.2.1]oct-3-yl]-exo-acetate by conventional techniques used in organic synthesis such as
crystallization, distillation or column chromatography.
4. The process as claimed in claim 3, wherein methyl (2S)-2-(benzyloxycarbonyl)-amino-2-[-8-
[benzyloxy carbonyl]-8-azabicyclo-[3.2.1]oct-3-yl]-exo-acetate is prepared by reaction of
methyl (2S)-2-amino-2-[8-azabicyclo-[3.2.1]oct-3-yl]-exo-acetate hydrochloride with
benzyloxy carbonyl chloride in the presence of aqueous sodium bicarbonate solution in
aqueous 1,4-dioxane at around 0°C followed by optional isolation and purification of methyl
(2S)-2-(benzyloxycarbonyl)-amino-2-[-8-[benzyloxy carbonyl]-8-azabicyclo-[3.2.1 ]oct-3-yl]-
exo-acetate by conventional techniques used in organic synthesis such as crystallization, distillation
or column chromatography.
5. The process as claimed in claim 4 wherein, methyl (2S)-2-amino-2-[8-azabicyclo-
[3.2.1]oct-3-yl]-exo-acetate hydrochloride is prepared by hydrogenolysis of l-(2-hydroxy-1-

(1R)-phenylethyl amino)-1-(8-(benzyloxy carbonyl) -8 -aza-bicyclo[3.2.1 ]-oct-3-yl)-exo-
methane-1-(1S)-carboxylic acid methyl ester hydrochloride over palladium supported on
charcoal at around 20 Kg pressure of hydrogen at a temperature of about 60°C in an organic
solvent such as methanolic hydrochloric acid followed by optional isolation and purification
of methyl (2S)-2-amino-2-[8-azabicyclo-[3.2.1]oct-3-yl]-exo-acetate hydrochloride by
conventional techniques used in organic synthesis such as crystallization, distillation or column
chromatography.
6. The process as claimed in claim 5 wherein, 1 -(2-hydroxy-1 -(1R)-phenylethyI amino)-1-(8-
(benzyloxy carbonyl) -8-aza-bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(1S)-carboxylic acid
methyl ester hydrochloride is prepared by a process comprising hydrolysis of the nitrile
group in 1-(2-hydroxy-1-(1R)-phenylethyl amino)-1-(8-(benzyloxy carbonyl)-8-aza-
bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(1S)-carbonitrile using methanolic-HCl at room
temperature followed by optional isolation and purification of 1 -(2-hydroxy-1 -(1R)-
phenylethyl amino)-1-(8-(benzyloxy carbonyl) -8-aza-bicyclo[3.2.1]-oct-3-yI)-exo-methane-
1-(1S)-carboxylic acid methyl ester hydrochloride by conventional techniques used in organic
synthesis such as crystallization, distillation or column chromatography.
7. The process as claimed in claim 6 wherein, 1-(2-hydroxy-1-(1R)-phenylethyl amino)-1-(8-
(benzyloxy carbonyl)-8-aza-bicyclo[3.2.1J-oct-3-yl)-exo-methane-1-(1S)-carbonitrile is
prepared by a process comprising of reaction of benzyl 3-exo-formyl-8-
azabicyclo[3.2.1]octane-8-carboxylate with R-(-)-2-Phenyl glycinol and trimethylsilylcyanide
in an organic solvent selected from dichloromethane, methanol, chloroform, 1,2-
ethylenedichloride, hexane, tetrahydrofuran, methyltetrahydrofuran, DME or mixtures
thereof under standard Strecker reaction conditions in the presence of acetic acid, or Lewis
acid at a temperature between -40 °C and 25 °C followed by optional isolation and
purification of 1-(2-hydroxy-1-(1R)-phenylethyl amino)-1-(8-(benzyloxy carbonyl)-8-aza-
bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(lS)-carbonitrile by conventional techniques used in
organic synthesis such as crystallization, distillation or column chromatography.
8. The process as claimed in claim 7 wherein, benzyl 3-exo-formyl-8-
azabicyclo[3.2.1]octane-8-carboxylate is prepared by a process comprising:

(a) reaction of 8-methyl-8-azabicyclo[3.2.1]octan-3-one with benzyl chloroformate in
presence of an inorganic base such as K2CO3 in a organic solvent such as toluene at
an ambient temperature to obtain benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-
carboxylate followed by optional isolation and purification of the product by
conventional techniques used in organic synthesis such as crystallization, distillation or
column chromatography;
(b) reaction of benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate with ylide obtained
by reaction of sodium hydride and trimethylsulfonium iodide in an organic solvent
such as dimethylformamide at room temperature to obtain benzyl 8H-spiro[8-
azabicyclo[3.2.1]octane-3,2'-oxirane]-8-carboxylate followed by optional isolation
and purification of the product by conventional techniques used in organic synthesis such
as crystallization, distillation or column chromatography;
(c) reaction of benzyl 8H-spiro[8-azabicyclo[3.2.1]octane-3,2'-oxirane]-8-carboxylate
with BF3-etherate in an organic solvent such as dichloromethane at room temperature
to obtain benzyl 3-exo-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate followed by
optional isolation and purification of the product by conventional techniques used in
organic synthesis such as crystallization, distillation or column chromatography.
9. A compound benzyl 3-exo-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate
10. A compound l-(2-hydroxy-1-(1R)-phenylethyl amino)-1-(8-(benzyloxy carbonyl)-8-aza-
bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(1S)-carbonitrile and salts thereof
11. A compound 1 -(2-hydroxy-1-(1R)-phenylethyl amino)-1-(8-(benzyloxy carbonyl)-8-aza-
bicyclof3.2.1]-oct-3-yl)-exo-methane-1-(1S)-carboxylic acid methyl ester and salts thereof
12. A compound methyl (2S)-2-amino-2-[8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate and salts
thereof
13. A compound methyl (2S)-2-(benzyloxycarbonyl)-amino-2-[-8-[benzyloxy carbonyl]-8-
azabicyclo[3.2.1 ]oct-3-yl]-exoacetate
14. A compound benzyl methyl (2S)-2-((tert-butoxycarbonyl)-[benzyloxy carbonyl]-amino)-2-[8-
(benzyloxy carbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate

15. A process for the synthesis of compound of formula n

wherein, Rl is selected from C1 to C4 alkyl or benzyl; comprising:
i. conversion of compound of formula 1 to compound of formula 9 by the
condensation of compound of formula 1 with an active methylene compounds
such as methyl or ethyl isocyanoacetate in the presence of sodium hydride (NaH)
in an aprotic solvent such as tetrahydrofuran (THF) or in 1,4-dioxane or any water
miscible cyclic ether at about a temperature between 0 and 10 °C;

Wherein, R is selected from C1 to C4 alkyl, substituted or unsubstituted benzyl,
substituted or unsubstituted phenyl, C1 to C4 alkyloxy, substituted or
unsubstituted benzyloxy, C1 to C6 alkylamino, C1 to C6 dialkylamino; and Rl is
selected from C1 to C4 alkyl or benzyl;
ii. conversion of compound of formula 9 to compound of formula 10 with exo
configuration by treatment with methanolic-HCl at around 0 °C;


Wherein, R is selected from C1 to C4 alkyl, substituted or unsubstituted benzyl,
substituted or unsubstituted phenyl, C1 to C4 alkyloxy, substituted or
unsubstituted benzyloxy, C1 to C6 alkylamino, C1 to C6 dialkylamino;and Rl is
selected from C1 to C4 alkyl or benzyl;
iii. conversion of compound of formula 10 to compound of formula 11 by first
treating compound 10 with either (S)-(-)-2-methyl-2-propane sulfinamide or with
(R)-(+)-2-methyl-2-propane sulfinamide in the presence of titanium(lV) ethoxide
at reflux temperature followed by further reduction of the intermediate ketimine
using a suitable reducing agent such as sodium borohydride or sodium triacetoxy
borohydride at room temperature;

Wherein, R is selected from C1 to C4 alkyl, substituted or unsubstituted benzyl,
substituted or unsubstituted phenyl, C1 to C4 alkyloxy. substituted or
unsubstituted benzyloxy, C1 to C6 alkylamino, C1 to C6 dialkylamino; Rl is
selected from C1 to C4 alkyl or benzyl, and R2 is (R/S) tert-C4H9-S*(O), wherein,
asterisk denotes point of attachment;
iv. conversion of compound of formula 11 to compound m first by treatment with
alcoholic-HCl, followed by treatment with di-tert-butyl dicarbonate, further
hydrogenolysis of compound of formula m over palladium supported on charcoal
(Pd/C) to give compound of formula n;


Such that at each step the intermediates were optionally isolated and purified with suitable
process.
16. A process for the synthesis of ethyl (2S)-2-(tert-butoxycarbonyl)-amino-2-[-8-azabicyclo
[3.2.1]oct-3-yl]-exoacetate comprising of
a. conversion of 1-(R or S -tert-butylsulfinylamino)-1-(8-(benzyloxy carbonyl)-8-aza-
bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(lS)-carboxylic acid ethyl ester to ethyl (2S)-
2-((tert-butoxycarbonyl)-amino)-2-[8-(benzyloxy carbonyl)-8-azabicyclo[3.2.1]oct-3-
yl]-exo-acetate first by treatment with methanolic-HCl, followed by reaction with di-
tert-butyl dicarbonate followed by optional isolation and purification of the product by
conventional techniques used in organic synthesis such as crystallization, distillation or
column chromatography;
b. hydrogenolysis of ethyl (2S)-2-((tert-butoxycarbonyl)-amino)-2-[8-(benzyloxy
carbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate over palladium supported on
charcoal (Pd/C) followed by isolation and purification of the product by conventional
techniques used in organic synthesis such as crystallization, distillation or column
chromatography.
17. The process as claimed in claim 16 wherein 1-(R or S -tert-butylsulfinylamino)-1-(8-
(benzyloxy carbonyl)-8-aza-bicyclo[3.2.1 ]-oct-3-yl)-exo-mefhane-l -(1S)-carboxylic acid
ethyl ester is prepared by a process comprising of treating benzyl exo-3-(ethoxy or methoxy
(oxo)acetyl]-8-azabicyclo[3.2.1]octane-8-carboxylate with either (R)-(+)-2-methyl-2-propane
sulfinamide or with (S)-(-)- 2-methyl-2-propane sulfinamide in the presence of titanium(IV)
ethoxide to obtain a ketimine intermediate followed by reduction of the ketimine
intermediate using a suitable reducing agent such as sodium borohydride or sodium
triacetoxy borohydride, wherein the ketamine intermediate and 1-(R or S -tert-
butylsulfinylamino)-l -(8-(benzyloxy carbonyl)-8-aza-bicyclo[3.2.1]-oct-3-yl)-exo-methane-
l-(1S)-carboxylic acid ethyl ester are optionally isolated and purified by conventional
techniques used in organic synthesis such as crystallization, distillation or column chromatography.
18. The process as claimed in claim 17 wherein benzyl exo-3-[ethoxy or methoxy
(oxo)acetyl]-8-azabicyclo[3.2.1]octane-8-carboxylate is prepared by a process comprising of

treating benzyl 3-( 1 -formamido-2-ethoxy-2-(oxo)ethylidene)-8-azabicyclo[3.2.1]-octane-8-
carboxylate with methanolic hydrochloric acid at around 0°C followed by optional isolation
and purification of the product by conventional techniques used in organic synthesis such as
crystallization, distillation or column chromatography.
19. The process as claimed in claim 18 wherein benzyl 3-(l-formamido-2-ethoxy-2-
(oxo)ethylidene)-8-azabicyclo[3.2.1]-octane-8-carboxylate is prepared by a process
comprising condensation of benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate with an
active methylene compounds such as methyl or ethyl isocyanoacetate in the presence of
sodium hydride (NaH) in an aprotic solvent such as tetrahydrofuran (THF) or in 1,4-dioxane
or any water miscible cyclic ether at about a temperature between 0 and 10 °C followed by
optional isolation and purification of the product by conventional techniques used in organic
synthesis such as crystallization, distillation or column chromatography.
20. A compound benzyl 3-(l-formamido-2-ethoxy-2-(oxo)ethylidene)~8-azabicyclo[3.2.1]-
octane-8-carboxylate.
21. A compound benzyl exo-3-[ethoxy or methoxy (oxo)acetyl]-8-azabicyclo[3.2.1]octane-8-
carboxylate.
22. A compound benzyl 3-[(1E/Z)-N-((R or S)-tert-butylsulfinyl)-2-ethoxy-2-
oxoethanimidoyl]-8-azabicyclo[3.2.1]octane-8-carboxylate.
23. A compound 1-((R or S)-tert-butylsulfinylamino)-1-(8-(benzyloxy carbonyl)-8-aza-
bicyclo[3.2.1]-oct-3-yl)-exo-methane-1-(1S)-carboxylic acid ethyl ester.
An improved process for the synthesis of various intermediates useful in the synthesis of
Dipeptidyl peptidase (DPPIV) inhibitors. The present invention relates to an improved
process for the preparation of a key intermediate viz. methyl (2S)-2-(tert-butoxycarbonyl)-
amino-2-[-8-azabicyclo[3.2.1]oct-3-yl]-exo-acetate (compound of formula n) useful for the
preparation of DPP-IV inhibitors, as schematically provided in 'Scheme - A'. The present
strategies disclosed in scheme 2 and 3 offers more practical, cost effective, safe and eco-
friendly process routes. While scheme 2 leads to the intermediate n in 8 steps, scheme 3
offers n in 6 steps.