Carmegliptin
Carmegliptin
Carmegliptin
pubs.acs.org/OPRD
ABSTRACT: 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 additionMannich 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 10 was coupled with (S)-fluoromethyl lactone 31. Following cyclization to
lactam 13 and amine deprotection, 1 was obtained in 2731% overall yield with six isolated intermediates.
1. INTRODUCTION overall yield. Besides the long linear sequence and the very low
Type 2 diabetes (T2D) is a disease characterized by high levels overall yield, several issues were identified in this synthesis: (i)
of blood glucose in the context of insulin resistance and relative selectivity in the Dieckmann cyclization (step 4); (ii) nonscalable
insulin deficiency. The disease has been classified by the Center hydride reduction (step 7); (iii) safety issues in the Curtius
for Disease Control and Prevention (CDC) as an epidemic, with rearrangement (step 10); (iv) optical resolution by preparative
the prevalence rates doubling over the past 15 years and expected HPLC on chiral stationary phase; (v) coupling of amine 10 with
to increase significantly worldwide, even in developing countries, rac-11 (step 10). This route was deemed unsuitable for large-
in the years to come.1 It is estimated that worldwide 285 million scale supply since it did not meet our criteria for safety,
people (6.6% of the population) suffer from diabetes.2 Inhibition robustness, and economical as well as ecological viability.
of dipeptidyl peptidase IV (DPP-IV) is a proven approach for the In this contribution, the efforts from Process Research and
treatment of T2D.3 DPP-IV is responsible for the degradation/ Process Development to devise a scalable route that addresses
deactivation of glucagon-like peptide 1 (GLP-1) by cleaving the the aforementioned issues and would allow for the production of
N-terminal two amino acids, resulting in reduced insulin carmegliptin on ton scale are described.8 Route exploration and a
secretion. scalable synthesis of the optically active fluoromethyl lactone 31
Carmegliptin4 (1) (Figure 1) is a new generation DPP-IV needed for the lactam side chain are described elsewhere.9
inhibitor developed at Roche, structurally distinct from earlier
drug candidates.5 The structure is characterized by a 2-amino-
2. RESULTS AND DISCUSSION
hexahydro-benzo[a]quinolizine core, featuring a densely func-
tionalized six-membered azacycle with three stereogenic centers 2.1. Decarboxylative Mannich AdditionMannich Cycli-
and all the substituents adopting an equatorial orientation.6 The zationEnamine Formation Sequence. In the Discovery
C-3 nitrogen is incorporated in a chiral lactam side chain Chemistry synthesis, the assembly of the tricyclic core was
possessing a fluoromethyl substituent in β-position which poses achieved by a Michael additionDieckmann cyclization seque-
a significant synthetic challenge. nce from rac-4. The Michael addition was found to exhibit a
The Discovery Chemistry route (Scheme 1) consists of a 21- high potential for a runaway behavior as a result of ethyl acrylate
step synthesis with a 16-step longest linear sequence.4b The (used in large excess) polymerization. For the first API delivery,
synthesis started with 2-(3,4-dimethoxyphenyl)ethylamine and the problem was solved by performing the Michael addition
its conversion to imine 3 by BischlerNapieralski reaction. in acetonitrile under copper(I) catalysis.10 Additionally, the
Decarboxylative malonate addition was followed by a 1,4-addi- Dieckmann cyclization suffered from poor regioselectivity (4:3
tion and a Dieckmann reaction7 to give the tricyclic enol ester mixture of desired/undesired regioisomers) necessitating tedi-
rac-6. The enamine formation, diastereoselective hydride reduc- ous isomer separation and resulted in moderate isolated yield. A
tion (establishing the relative configuration of all three stereo- more efficient access to (()-enamine 7 was required.
centers), and Curtius rearrangement (introducing the C-3 The synthesis of the enaminoester rac-7 by double Mannich
nitrogen functionality) provided the bis-protected diamine rac- reaction had already been reported starting from acetone dicar-
9. Teoc (trimethylsilylethyl carbamate) cleavage and chiral boxylic acid (Scheme 2).11 This approach was briefly evaluated
HPLC separation afforded enantiopure amine 10 in ∼5% yield but not further pursued as the thermal stability of the amino acid
from amine 2. The lactam moiety was introduced by coupling of
amine 10 with acid chloride rac-11 and cyclization. Boc depro- Received: January 25, 2011
tection and crystallization finally led to carmegliptin in about 2% Published: May 05, 2011
r 2011 American Chemical Society 503 dx.doi.org/10.1021/op2000207 | Org. Process Res. Dev. 2011, 15, 503–514
Organic Process Research & Development ARTICLE
a
Reagents 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.
To investigate the mechanism of the underlying racemization Scheme 2. Initial double-Mannich route to enol ester rac-6
process, trapping experiments were designed based on the
hypothesis that ring-opened intermediates are involved and
may be trapped using a suitable reducing agent. Indeed, earlier
experiments showed a slight erosion of enantiomeric purity
during the subsequent hydride-mediated reduction of enamine
(S)-7 to the corresponding amine, suggesting that scrambling of
the stereogenic center is operative under these conditions. Thus,
(S)-7 was treated with trifluoroacetic acid (TFA) followed by
addition of NaBH4. The resulting mixture was treated with
Boc2O in dichloromethane to facilitate isolation of byproducts
formed in trace amounts. The results of these experiments, which
led to the isolation of ring-opened 22, clearly favor the mecha-
nisms depicted in Scheme 5.
2.3. Synthesis of Boc-Protected Amine 25. The subsequent
reduction of the dibenzoyltartaric acid salt (S)-20 with NaBH4
and TFA establishes two additional stereogenic centers, making
it one of the key transformations of the overall synthesis. The
reaction conditions developed by Discovery Chemistry (TFA,
THF, rt, then NaBH4) led to 25 with good diastereoselectivity
following Boc protection, and the undesired diastereomers were
depleted by crystallization from heptane. However, these condi- To avoid these drawbacks, a scalable protocol was devised for
tions prescribed the addition of NaBH4 in one portion to a the first supply campaigns (up to several kg), which consisted in
solution of the enamine and TFA (40 equiv) to avoid the the preformation of a solution of enamine salt (S)-20 and TFA
formation of byproducts that were observed if the addition was (10 equiv) in THF followed by addition of this solution to a
performed portionwise. The resulting uncontrollable foaming suspension of NaBH4 in THF below 10 °C. It is worth noting
and vigorous hydrogen evolution limited this procedure to that the reaction proceeded equally well using the dibenzoyltar-
laboratory scale. taric acid salt (S)-20 instead of the free base (S)-7. Excess TFA
505 dx.doi.org/10.1021/op2000207 |Org. Process Res. Dev. 2011, 15, 503–514
Organic Process Research & Development ARTICLE
a
Reagents and conditions: a) Ac2O, AcOH, 1015 °C; b) EtOH, heptane, rt; c) NaOAc (0.1 equiv), MeOH/H2O, rt; d) aq CH2O, MeOH, rt; e)
NH4OAc, MeOH, 50 °C.
a
Reagents and conditions: a) i. TFA, THF, rt; ii. NaBH4, rt; iii. Boc2O,
CH2Cl2, rt.
Scheme 6. Stereoisomers obtained by hydride-mediated enamine reduction following treatment with Boc2O
Scheme 7. Telescoped three-step process to amide 28 Scheme 9. Telescoped three-step process to fluoromethyl
lactam 13
Reagents and conditions: a) 16, NaOAc (0.1 equiv), MeOH, H2O; b) aq CH2O, MeOH rt then NH4OAc, 50 °C; c) (þ)-DBTA, EtOH, 60 °C, 15 h; d)
i) NaBH4, F3CCO2H, THF, 10 °C to rt; ii) Boc2O, PhMe/H2O, 5 °C to rt, (pH 10); iii) NaOMe, HCONH2, THF, 35 °C, then crystallization from
H2O/MeOH; e) PIDA, KOH, MeCN/H2O, 2428 °C, then crystallization from PhMe; f) i) 31 (1.3 equiv), 6-chloro-2-pyridinol (0.1 equiv), PhMe,
11085 °C; ii) MsCl, Et3N, THF, 2230 °C; iii) t-BuOLi, THF, 10 to 0 °C, then crystallization from MeOH; g) HCl, acetone/H2O, 50 °C.
conversions were determined by HPLC (% by area). Enantio- cake was dried at 45 °C/2030 mbar until constant weight to
meric excesses (ee) were determined by HPLC on chiral give 42 kg of the title compound (81% yield, 96% by area
stationary phase using the indicated conditions. 1H NMR spectra (HPLC) and 0.2% (w/w) residual EtOH). The product may
were recorded at 400 MHz using tetramethylsilane (TMS) as contain up to 1.8% (w/w) NaCl.
internal reference. Data are presented as follows: chemical shift 1
H NMR (400 MHz, DMSO-d6) δ 1.20 (t, J = 7.3 Hz, 3H),
(δ) in ppm, multiplicity (s = singlet, d = doublet, t = triplet, q = 2.833.01 (m, 2H), 3.183.35 (m, 2H), 3.34 (dd, J = 19 and 4
quartet, m = multiplet, br = broad), coupling constants (J) in Hz, Hz, 1H), 3.46 (dd, J = 19 and 8 Hz, 1H), 3.68 (d, J = 19 Hz, 1H),
and integration. 13C NMR spectra were recorded at 100 MHz. 3.71 (s, 3H), 3.73 (s, 3H), 3.77 (d, J = 19 Hz, 1H), 4.12 (t, J = 7
Absorptions in IR spectra are recorded in wavenumbers (cm1). Hz, 2H), 4.76 (br dd, J = 8 and 4 Hz, 1H), 6.77 (s, 3H), 6.78 (s,
Low-resolution mass spectra were obtained by positive or 3H). MS ESI: m/z 322.2 ([M þ H]þ)
negative ion spray ionization (ESI). Data are reported in the 4.4. Preparation of (()-2-Amino-9,10-dimethoxy-1,6,7,11b-
form of m/z. tetrahydro-4H-pyrido[2,1-a]isoquinoline-3-carboxylic Acid
4.2. Preparation of Pyran-2,4,6-trione (18). Acetone dicar- Ethyl Ester (rac-7). Ketoester hydrochloride 15 (2.60 kg, 7.19
boxylic acid (32.5 kg, 222 mol, 1.00 equiv) was charged in the mol, 1.00 equiv) was charged in the reactor and dissolved by
reactor followed by AcOH (46 L). The suspension was cooled to addition of MeOH (15 L). A solution of NaOAc (0.590 kg, 7.19
1520 °C, and Ac2O (35 L) was added. The reaction mixture mol, 1.00 equiv) in MeOH (6 L) was added. The addition system
was stirred for 45 h at 810 °C. A solution was obtained during was rinsed with MeOH (3 L). The obtained solution was
the course of the reaction after which the product started to transferred in a feed tank, and the reactor and transfer lines were
crystallize. The resulting suspension was filtered, and the filter rinsed with MeOH (5 L). The resulting solution was added at
cake was washed with PhMe (65 L) and dried at 45 °C/30 mbar 2025 °C over 2530 min to a solution of 37% aq CH2O (0.58
to give 22.5 kg of the title compound (79% yield). L, 7.55 mol, 1.05 equiv) in MeOH (13 L). The feed tank and
1
H NMR (400 MHz, DMSO-d6) δ 3.68 (s, 2H), 5.23 (s, 1H), transfer lines were rinsed with MeOH (10 L). The reaction
12.5 (br s, 1H). mixture was stirred for 45 h at 2025 °C (IPC indicated
4.3. Preparation of (Z)-4-(6,7-Dimethoxy-1,2,3,4-tetrahy- conversion to intermediate rac-6), whereupon NH4OAc (1.7 kg,
dro-isoquinolin-1-yl)-3-hydroxy-but-2-enoic Acid Ethyl Es- 21.6 mol, 3.0 equiv) was added. The reaction mixture was heated
ter Hydrochloride (15). Cyclic anhydride 18 (22.3 kg, 174 mol, to 4550 °C overnight and then cooled to 2025 °C. The
1.20 equiv) was suspended in heptane (83 L) at room tempera- resulting red reaction mixture was concentrated under pressure
ture. EtOH (58 L) was added dropwise over 1520 min while at ∼2530 °C to an oily residue which was taken in CH2Cl2 (22
maintaining the temperature between 2025 °C. After 1 h L) and H2O (11 L). The resulting pH 56 was adjusted to pH >
reaction, the resulting clear solution was transferred to a feed 7 by addition of aq NaHCO3 (1.5 kg in 15 L water). The organic
tank. The reactor and the lines were rinsed with EtOH. The phase was separated and washed with aq NaCl (1.7 kg in 15 L
resulting solution was added over 1.5 h to a turbid solution water). The aqueous phases were re-extracted with CH2Cl2 (20
consisting of imine hydrochloride 3 (33.0 kg, 145 mol, 1.0 equiv), L). The organic phases were combined, and solvent was ex-
NaOAc (1.20 kg, 14.5 mol, 0.10 equiv), H2O (8.5 L), and EtOH changed to MeOH (7 L final MeOH volume). The resulting
(250 L) while keeping the temperature between 2025 °C. suspension was dissolved at reflux. The solution was cooled over
Crystallization of the product was usually observed during the 15 h to 25 °C to 20 °C and stirred for 5 h. The suspension
reaction. After 1.5 h, 37% aq HCl (1.5 L, 17 mol, 0.12 equiv) was was filtered, and the filter cake was washed with cold (25 °C)
added to the resulting suspension. Heptane (240 L) was added MeOH (4 L) and cold (25 °C) heptane (1.6 L). The crystals
over 30 min. The yellow suspension was cooled and stirred for 2 were dried under reduced pressure at 35 °C to give 1.83 kg of the
h at 05 °C. The suspension was filtered and washed with a cold title compound (71%, 97% by area (HPLC), 7.4% (w/w)
(0 °C) mixture of EtOH (55 L) and heptane (110 L). The filter residual MeOH).
510 dx.doi.org/10.1021/op2000207 |Org. Process Res. Dev. 2011, 15, 503–514
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1
H NMR (400 MHz, CDCl3) δ 1.28 (t, J = 7.3 Hz, 3H), 2025 °C within 30 min and stirred at this temperature for 100 min.
2.402.72 (m, 4 H), 3.033.16 (m, 3 H), 3.433.52 (m, 3 H), During the entire reaction time the pH was kept constant at pH
3.73 (d, J = 13.7 Hz, 1 H), 3.86 (s, 6 H), 4.18 (m, 2 H), 6.59 (s, 1 ∼10 by the careful addition of 50% aq KOH (16 kg in total).
H), 6.60 (s, 1 H). 13C NMR (150 MHz, CDCl3) δ 168.56, Upon complete conversion (<0.5% by area (HPLC) of free amine),
154.24, 147.68, 147.46, 128.68, 126.92, 111.47, 108.25, 91.05, the stirrer was stopped, and the biphasic mixture was allowed to
59.05, 58.04, 56.10, 55.86, 53.67, 50.99, 37.56, 28.94, 14.62. separate for 20 min. The lower aqueous layer was separated and
HRMS (ESI): m/z 333.1 ([M þ H]þ); Expected mass: extracted with PhMe (240 kg). The combined organic layers were
332.1736; Found: 332.1734 (calculated for M). washed with H2O (180 kg) and concentrated under reduced
4.5. Preparation of (S)-2-Amino-9,10-dimethoxy-1,6,7,11b- pressure at 3050 °C to almost dryness. The residue was treated
tetrahydro-4H-pyrido[2,1-a]isoquinoline-3-carboxylic Acid with THF (400 kg), and the resulting mixture was concentrated
Ethyl Ester, (S,S)-2,3-Bisbenzoyloxy-succinic Acid Salt ((S)- at 3050 °C under reduced pressure to almost dryness. The residue
20). A 160-L Hastelloy reactor was charged with enamine rac-7 was diluted with THF (1500 kg), and the mixture was concentrated
(27.7 kg, 74.5 mol, containing ∼8% (w/w) MeOH) and EtOH at 3050 °C under reduced pressure to a residual volume of 1400
(97 L). (S,S)-(þ)-Dibenzoyl-D-tartaric acid (28.5 kg, 79.5 mol, 1500 L. In the case of a complete solvent exchange (<0.10% (w/
1.06 equiv) was added under stirring followed by EtOH (41 L) to w) H2O, <8.0% (w/w) PhMe) the residue was treated at
give an off-white suspension. The mixture was heated to 60 °C 3238 °C first within 10 min with formamide (131 kg, 2902
over 45 min and stirred at this temperature for 24 h. The thick mol, 10.0 equiv) and subsequently within 1 h with 30% NaOMe
yellowish suspension was cooled to ambient temperature over 8 in MeOH (156 kg, 868 mol, 3.0 equiv). The mixture was stirred
h and filtered. The crystals obtained were washed with EtOH (82 at 35 °C for 12 h. Upon complete conversion (<0.5% by area
L, 0 °C) and dried under reduced pressure at 45 °C for 24 h to (HPLC) of ethyl ester 25 and <3.0% of the corresponding
give 48.1 kg (93%, ee >99.5%) of the title compound as white methyl ester), the suspension was treated with H2O (740 kg).
crystals. The mixture was concentrated at 3055 °C under reduced
1
H NMR (400 MHz, DMSO-d6) δ 1.20 (t, J = 7.2 Hz, 3H), pressure to a residual volume of 12001250 L. The suspension
2.412.29 (m, 1H), 2.682.59 (m, 1H) 2.862.72 (m, 1H), was diluted with MeOH (550 kg), and the resulting mixture was
3.022.90 (m, 1H), 3.153.05 (m, 1H), 3.403.27 (m, 2H), heated at 60 °C for 10 h. The suspension was cooled to 30 °C and
3.71 (s, 3H), 3.72 (s, 3H), 3.853.75 (m, 1H), 3.963.85 (m, subsequently centrifuged immediately. The crystals were washed
1H), 4.08 (q, J = 7.2 Hz, 2H), 5.74 (s, 2H), 6.62 (s, 1H), 6.81 (s, in two portions with a mixture of H2O (86 kg) and THF (66 kg)
1H), 7.587.53 (m, 4H), 7.737.66 (m, 2H), 8.037.96 (m, and dried at 70 °C and <30 mbar for 10 h to afford 100.4 kg
4H), 14.1 (br. s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 14.5, (85%) of the title amide 28 as colorless crystals with an assay
26.8, 34.7, 49.5, 52.0, 55.4, 55.7, 57.1, 58.4, 71.7, 85.0, 109.0, (HPLC) of 97.8% (w/w).43
111.6, 125.1, 126.0, 128.8, 129.0, 129.3, 133.7, 147.4, 147.8, 1
H NMR (400 MHz, DMSO-d6) δ 1.171.25 (m, 1H), 1.38
155.6, 164.7, 167.0, 167.5. IR (cm1): 3440, 3320, 2924, 2854, (s, 9H), 2.302.49 (m, 4H), 2.522.62 (m, 1H), 2.762.97 (m,
1734, 1618, 1376, 1260, 1237, 1129, 1027, 769, 714. MS (ESI): 3H), 3.073.12 (m, 1H), 3.70 (s, 3H), 3.71 (s, 3H), 3.653.75
m/z 333.1 ([M þ H]þ free amine). Anal. Calcd for (m, 1H), 6.616.71 (m, 3H), 6.84 (br s, 1H), 7.04 (br s, 1H). IR
C36H38N2O12: C, 62.6; H, 5.55; N, 4.06. Found: C, 62.45; H, (cm1): 3446, 3346, 2923, 1684, 1663, 1535. MS (ESI): m/z
5.82; N, 3.77. [R]20D = 133.7° (c 1.025, DMSO). Chiral 406.2 ([M þ H]þ). Anal. Calcd for C21H31N3O5: C, 62.20; H,
HPLC: Chiralpak OD-RH column (5 μm, 250 4.6 mm), 7.71; N, 10.36. Found: C, 62.09; H, 7.76; N, 10.39.
MeCN/H2O: aq NaClO4 (0.5 M) 0.714:0.026:0.26, flow rate: 4.7. Preparation of (2S,3S,11βS)-3-(Amino-9,10-dimethoxy-
1.0 mL min1, oven temperature: 40 °C, detection: 210 nm, Rt: 1,3,4,6,7,11β-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-
14.0 min (R), 15.6 min (S). carbamic Acid tert-Butyl Ester (10). A suspension of amide 28
4.6. Preparation of (2S,3S,11βS)-3-(Carbamoyl-9,10-di- (120 kg, 296 mol) in a mixture of H2O (1000 kg) and MeCN
methoxy-1,3,4,6,7,11β-hexahydro-2H-pyrido[2,1-a]isoqui- (522 kg) was treated within 30 min at 1528 °C with 50% aq
nolin-2-yl]-carbamic Acid tert-Butyl Ester (28). A 1000-L KOH (166.0 kg, 1479 mol, 5 equiv) and the resulting suspension
reactor was charged under a nitrogen atmosphere with NaBH4 stirred at 2428 °C for 30 min. To the suspension was added
(14.8 kg, 391 mol, 1.35 equiv) and THF (550 kg). The suspen- within 34 h at 2428 °C a solution of iodosobenzene diacetate
sion was treated at 17 to 10 °C within 4 h with TFA (162 kg, (106 kg, 329 mol, 1.10 equiv) in a mixture of H2O (270 kg) and
1421 mol, 5.0 equiv). (S)-20 (200 kg, 290 mol) was added as a MeCN (448 kg). After the addition, the suspension was stirred at
solid to the suspension within 5 h at 15 to 10 °C. The starting 2428 °C for 1 h. Upon complete conversion (<0.1% by area
material container and the transfer lines were rinsed with THF (HPLC) of starting material), the suspension was concentrated
(100 kg). The reaction mixture was heated to 0 °C within 3 h and under reduced pressure and at a maximum internal temperature
stirred at this temperature for 3 h. The reaction mixture was of 45 °C (70 °C jacket temperature) to a residual volume of
heated to 20 °C within 3 h and stirred at this temperature for 5 h. approximately 1200 L. The pH of the mixture was adjusted to pH
Upon complete conversion (<1.0% by area (HPLC) of starting 9.5 by treatment with 37% aq HCl (33.8 kg) at 2040 °C. THF
material), the reaction was transferred in a 2500-L vessel and (210 kg) and PhMe (1040 kg) were added at 2040 °C, and the
quenched by the addition of H2O (658 kg). The mixture was resulting mixture was heated to 7075 °C and stirred at this
stirred at 2025 °C for 30 min and then cooled to 510 °C. The temperature for 3060 min. The agitator was stopped, and the
pH of the mixture was adjusted at this temperature from biphasic mixture was allowed to separate for 30 min. The lower
approximately 1.8 to 11.011.5 by the careful addition of 50% aqueous layer was discharged and the organic layer washed with
aq KOH (187 kg). The mixture was treated at 510 °C within H2O (180 kg) at 7075 °C. From the organic layer, THF and
30 min with a solution of Boc2O (80.5 kg, 369 mol, 1.27 equiv) in H2O were removed by azeotropic distillation with PhMe at a
PhMe (40.0 kg). The receiver and the transfer lines were rinsed maximum internal temperature of 70 °C. At the end of the
with PhMe (73 kg). The reaction mixture was allowed to warm to distillation the THF content should be <0.5%, and the volume of
511 dx.doi.org/10.1021/op2000207 |Org. Process Res. Dev. 2011, 15, 503–514
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the mixture was adjusted to 17001800 L. The mixture was layer was concentrated at <40 °C under reduced pressure to a
heated to 7080 °C to obtain a dimmish solution. To remove residual volume of 150 L. MeOH (950 kg) was added and the
the urea byproduct 30, the solution was filtered at 7080 °C. mixture concentrated at <40 °C under reduced pressure to a
The first reactor, the filter, and the transfer lines were rinsed with residual volume of 500530 L. The resulting suspension was
hot PhMe (400 kg). The filtrate was concentrated at a maximum heated to reflux temperature (∼65 °C) and stirred at this
internal temperature of 80 °C under reduced pressure to a temperature for 3060 min to obtain a clear (or dimmish)
residual volume of 10001100 L, whereby the product partly solution. The mixture was allowed to cool to 10 °C within 5 h
precipitated. The suspension was heated to 90 °C to obtain a and the resulting suspension stirred for 2 h at 10 °C. The
clear solution. The solution was cooled to 8 °C within 7 h and crystals were centrifuged, subsequently washed in portions with a
subsequently stirred at this temperature for 2 h. The crystals were cooled mixture (5 °C) of MeOH (81 kg) and H2O (51 kg), and
filtered off using a centrifuge, washed in two portions with cooled dried at 4550 °C/< 30 mbar to afford 88.8 kg (78% yield) of the
PhMe (<0 °C; 300 L), and dried at 60 °C/<30 mbar for 7 h to title compound as colorless to slightly yellow crystals with an
afford 94.6 kg (85%) of amine 10 as slightly yellow crystals with assay (HPLC) of 99.1% (w/w). 1H NMR (400 MHz, DMSO-d6)
an assay (HPLC) of 99.8% (w/w) with <0.10% of the corre- δ 1.37 (s, 9H); 1.371.49 (m, 1H); 2.072.15 (m, 1H);
sponding enantiomer (by chiral HPLC). 2.222.32 (m, 1H); 2.332.65 (m, 5H); 2.722.78 (m, 1H);
1
H NMR (400 MHz, CDCl3) δ 1.26 (br s), 1.34 (q, J = 12 Hz, 2.812.92 (m, 2H); 3.023.17 (m, 2H); 3.633.76 (m, 2H);
1H), 1.49 (s, 9H), 2.19 (t, J = 12 Hz, 1H), 2.482.66 (m, 3H), 3.70 (s, 3H); 3.71 (s, 3H); 3.853.93 (m, 1H); 4.334.42 (m,
2.672.75 (m, 1H), 2.922.99 (m, 1H), 3.013.15 (m, 2H), 1H); 4.454.55 (m, 1H); 6.64 (s, 1H); 6.78 (s, 1H); 6.92 (d, J =
3.183.24 (m, 1H), 3.393.51 (m, 1H), 3.837 (s, 3H), 3.844 (s, 8 Hz, NH). IR (cm1): 3401, 2926, 2854, 1696, 1512, 1466,
3H), 4.55 (br s), 6.57 (s, 1H), 6.66 (s, 1H). IR (cm1): 3355, 1010, 982. MS (ESI): m/z 478.1 ([M þ H]þ). Anal. Calcd for
2923, 2854, 1679, 1523, 1463, 1251. MS (Ion Spray) m/z 378.4 C25H36FN3O5: C, 62.87; H, 7.60; N, 8.80. Found: C, 62.49; H,
(MHþ). Anal. Calcd for C20H31N3O4: C, 63.64; H, 8.28; N, 7.56; N, 8.67.
11.13. Found: C, 63.77; H, 7.97; N, 11.15. Chiral HPLC: 4.8.2. Using t-BuOLi as Base for Cyclization. A 1500-mL
Chiralpak AD-H column (5 μm, 250 4.6 mm), n-heptane/ reactor equipped with a mechanical stirrer, a Pt-100 thermo-
isopropanol (with 0.1% NHEt2) 60:40, flow rate: 1.0 mL min1, meter, a dropping funnel, and a nitrogen inlet was charged with
oven temperature: 30 °C, pressure: 76 bar, detection: 210 nm, Rt: amine 10 (30.0 g, 79.5 mmol) and 6-chloro-2-pyridinol (1.20 g,
4.8 min ((R)-10), 6.4 min ((S)-10). 9.10 mmol) in PhMe (480 g). The mixture was heated to
4.8. Preparation of (2S,3S,11βS)-3-((4S)-Fluoromethyl-2- 8590 °C, and (S)-fluoromethyl lactone 31 (12.2 g, 103 mmol)
oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11β-hexahy- was added within 60 min. After the addition, the mixture was
dro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic Acid tert- heated to 105 °C and stirred at this temperature for 6 h.
Butyl Ester (13). 4.8.1. Using LHMDS as Base for Cyclization. A
Approximately 300 mL of PhMe were distilled off, and the
solution of amine 10 (90.0 kg, 238 mol) and 6-chloro-2-pyridinol
resulting thick suspension (250300 mL) was stirred at 85 °C
(3.60 kg, 27.8 mol, 0.120 equiv) in anhydrous PhMe (1180 kg)
for another 13 h. One hundred milliliters of PhMe were distilled
was heated to 8590 °C and treated at this temperature within
off and replaced by 400 g of THF. At the end of the distillation a
60 min with (S)-fluoromethyl lactone 319 (36.6 kg, 310 mol, 1.30
equiv, 99.099.5% ee). After the addition, the mixture was reaction volume of 500 mL was adjusted. The mixture was cooled
heated to 105 °C and stirred at this temperature for 7 h. to 23 °C and treated at 2330 °C with methanesulfonyl chloride
Approximately 570 kg of PhMe were distilled off at 7090 °C (13.8 g, 0.120 mol) followed by Et3N (14.0 g, 0.140 mol). The
under reduced pressure and the resulting suspension (800850 resulting thick suspension was allowed to stir at 2530 °C for 75
L) was subsequently stirred at 85 °C for another 12 h. Upon min, cooled to 10 to 0 °C, and subsequently treated at this
complete conversion (<1.0% starting material) the reaction temperature within 2 h with t-BuOLi (20% in THF, 95.0 g, 0.240
mixture is concentrated to a residual volume of ∼500 L. The mol). After addition completion, the suspension was stirred for 2
residue is diluted with THF (1200 kg) and subsequently con- h at 5 °C. The mixture was treated at <0 °C within 30 min with
centrated to a residual volume of ∼1600 L. The water-free H2O (70 g). The layers were allowed to separate at 05 °C for 30
suspension was cooled to 2325 °C and treated at a maximum min, and the aqueous layer was subsequently discharged. The pH
temperature of 30 °C with methanesulfonyl chloride (40.8 kg, of the organic layer was adjusted to pH 10.2 with 3% aq H2SO4
356.0 mol, 1.50 equiv) followed by Et3N (41.0 kg, 405 mol, 1.70 (∼32 g). H2O (38 g) was added, and the layers were allowed to
equiv) within 45 min. The resulting thick suspension was stirred separate at 05 °C for 20 min. The aqueous layer was removed,
at 2530 °C for 75 min. Upon complete mesylation (<1.5% and the organic layer was washed at room temperature with H2O
hydroxybutyramide 32), the reaction mixture was cooled to 10 (70 g). The two aqueous phases were combined and extracted
to 0 °C and subsequently treated at this temperature within 2 h with PhMe (65 g). From the combined organic layers THF and
with LHMDS (23.8% in THF, 503 kg, 715 mol, 3.00 equiv). After PhMe were completely distilled off and replaced by MeOH (300
complete addition, the resulting dimmish solution was stirred for g in total). At the end of the solvent exchange a volume of
additional 2 h at 5 °C. Upon reaction completion (<0.2% ∼200 mL was adjusted in the reactor. The resulting suspension
mesylate 33) the reaction mixture was treated at 5 to 5 °C was heated to reflux temperature and stirred at this temperature
within 1 h with H2O (220 kg). The layers were allowed to for 3060 min to obtain a clear solution. The solution was
separate at 05 °C for 30 min and the aqueous layer was allowed to cool to 10 °C within 57 h and the resulting
subsequently discharged. The organic layer was washed at suspension stirred for 2 h at 10 °C. The crystals were filtered
05 °C twice with 5% aq H2SO4 (2 240 kg). Both combined off, washed with a cooled mixture (5 °C) of MeOH (30 g) and
aqueous layers were back extracted with PhMe (195 kg). The H2O (10 g) and dried at 45 °C/< 30 mbar to afford 30.0 g (79%
combined organic layers were concentrated to a residual volume yield) of the title product as colorless crystals with an assay
of 700800 L and washed once with H2O (95 kg). The organic (HPLC) of 99.2% (w/w).
512 dx.doi.org/10.1021/op2000207 |Org. Process Res. Dev. 2011, 15, 503–514
Organic Process Research & Development ARTICLE
4.9. Preparation of (2S,3S,11βS)-1-(2-Amino-9,10-dimeth- Mattei, P.; Narquizian, R.; Wessel, H. P. (F. Hoffmann-La Roche AG).
oxy-1,3,4,6,7,11β-hexahydro-2H-pyrido[2,1-a]isoquinolin- U.S. Pat. Appl. 2004/0259902, 2004.
3-yl)-(4S)-fluoromethyl-pyrrolidin-2-one Dihydrochloride (5) For an overview on DPP-IV inhibitor syntheses, see: Mulakayala,
(1). A suspension of carbamate 13 (136 kg, 285 mol) in a mixture N.; Reddy, C. H. U.; Iqbal, J.; Pal, M. Tetrahedron 2010, 66, 4919.
of H2O (112 kg) and acetone (122 kg) was treated at 50 °C (6) The coupling constant between H2 and H3 is J = 11.5 Hz, which
within 60 min with 37% aq HCl (98.0 kg). After 90 min at is typical for a diaxial orientation of these protons.
(7) Brossi, A.; Lindlar, H.; Walter, M.; Schnider, O. Helv. Chim. Acta
4752 °C the solution was polish filtered through a 5 μm filter.
1958, 41, 119.
The first reactor and the transfer lines were washed with a hot (8) Abrecht, S.; Adam, J.-M.; Fettes, A.; Hildbrand, S. (F. Hoffmann-La
(4752 °C) mixture of H2O (13.0 kg) and acetone (116 kg). Roche AG). PCT Int. Appl. WO/2008/031749 A1, 2008. Bromberger, U.;
The filtrate was cooled to 25 °C and treated at this temperature Diodone, R.; Hildbrand, S.; Meier, R. (F. Hoffmann-La Roche AG). PCT
within 80 min with acetone (1600 kg) whereupon the product Int. Appl. WO/2009/027276 A1, 2009.
crystallized out. The resulting suspension was stirred for 1 h at (9) Details on the synthesis of the requisite (S)-fluoromethyl lactone
25 °C and subsequently centrifuged. The crystals were washed in 31 are described elsewhere: Adam, J.-M.; Foricher, J.; Hanlon, S.; Lohri,
two portions with acetone (391 kg) and dried at 50 °C and <30 B.; Moine, G.; Schmid, R.; Stahr, H.; Weber, M.; Wirz, B.; Zutter, U. Org.
mbar until constant weight to afford 122.4 kg (95%) of the title Process Res. Dev. 2011, 15, DOI: 10.1021/op200019k.
compound as colorless crystals with an assay (HPLC) of 98.8% (10) Xu, L. W.; Li, J.-W.; Xia, C.-G.; Hu, X.-X. Synlett 2003, 2425.
(11) (a) Chapman, J. H.; Holton, P. G.; Ritchie, A. C.; Walker, T.;
(w/w).
Webb, G. B.; Whiting, K. D. E. J. Chem. Soc. 1962, 2471. (b) Schneider,
1
H NMR (400 MHz, D2O) δ 2.112.22 (m, 1H); 2.45 (dd, W.; K€ammerer, E.; Schilken, K. Pharmazie 1966, 26.(c) Walker T.;
J = 17.6 Hz, 6.7 Hz; 1H); 2.76 (dd, J = 17.6 Hz, 9.55 Hz, 1H); England W.; Frederick K.; Rhondda M.; Wales G.; Ritchie A. C. U.S.
2.903.05 (m, 1H); 3.083.19 (m, 2H); 3.243.36 (m, 1H); Patent 3,105,835, 1963.
3.43 (dd, J = 9.8 Hz, 5.75 Hz, 1H); 3.493.58 (m, 1H); (12) Decomposition was observed at room temperature as also
3.703.84 (m, 4H); 3.87 (s, 3H); 3.88 (s, 3H); 4.12 (td, J = previously observed in the literature; see reference 9.
11.6 Hz, 4.5 Hz, 1H); 4.454.55 (m, 1H); 4.564.68 (m, 3H); (13) (a) The cyclic anhydride is mainly in the enol form in DMSO-
6.91 (s, 1H), 6.95 (s, 1H). IR (cm1): 3237, 2925, 1682, 496, d6. For keto-enol form analytical data see also:Kiang, A. K.; Tan, S. F.;
478. MS (ESI): m/z 378.3 ([M þ H]þ (free amine)). Anal. Wong, W. S. J. Chem. Soc (C) 1971, 2721. (b) For earlier
Calcd for C20H30Cl2FN3O3: C, 53.34; H, 6.71; N, 9.33; Cl, preparations see: Findlay, S. P. J. Org. Chem. 1957, 22, 1385–1394.
15.74; F 4.22; O, 10.66. Found: C, 53.04; H, 6.43; N, 9.45; Cl, Ray, J. A.; Harris, T. M. Tetrahedron Lett. 1982, 23, 1971. Kozikowski,
A. P.; Schmiesing, R. Tetrahedron Lett. 1978, 19, 4241.Ruminski P. G.;
15.66; F, 4.29; O, 11.09. Dhingra O. P. U.S. Patent 4,747,871. Sharma, V. K.; Shahriari-Zavareth,
H.; Garratt, P. J.; Sondheimer, F. J. Org. Chem. 1983, 48, 2379. Meltzer,
’ AUTHOR INFORMATION P. C.; Wang, B.; Chen, Z.; Blundell, P.; Jayaraman, M.; Gonzales, M. D.;
George, C.; Madras, B. K. J. Med. Chem. 2001, 44, 2619 and references
Corresponding Author cited therein.
[email protected]. (14) Precharging of the diacid in acetic acid led to clump formation.
(15) For reviews on crystallization-induced dynamic transforma-
Notes tions, see: (a) Brands, K. M. J.; Davies, A. J. Chem. Rev. 2006, 106, 2711.
§
See the accompanying paper in this issue by Adam et al. (b) Kolarovic, A.; Berkes, D. A.; Baran, P.; Povazanec, F. Tetrahedron
(DOI: 10.1021/op200019k). Lett. 2005, 46, 975. (c) Berkes, D.; Jakubec, P.; Winklerova, D.;
Povazanec, F.; Daich, A. Org. Biomol. Chem. 2007, 5, 121.
(16) (a) Openshaw, H. T.; Whittaker, N. J. Chem. Soc. 1963, 1461.
’ ACKNOWLEDGMENT (b) Clark, R. D.; Kern, J. R.; Kurz, L. J.; Nelson, J. T. Heterocycles 1990,
31, 353.
We thank Dr. T. Glarner, Dr. C. Lautz and their teams for (17) Dibenzoyltartaric acid was preferred over dibenzoyltartaric acid
process calorimetry and safety evaluations; Dr. N. Burki and J.-C. monodimethylamide for cost reasons.
Jordan as well as their teams for analytical support; M. S. (18) Temperatures higher than 60 °C for extended periods of time
Baumgartner, R. Benz, M. Christ, T. Gasser, M. Hohler, M. led to decomposition of the resolving agent.
Lander, P. M€uhlethaler, T. Naber, A. Saladin, G. Schaffner, K. (19) The kinetic studies were performed on a Multimax ART
Sch€onb€achler, C. Weber, and D. Zurwerra for their skillful workstation (Mettler-Toledo) equipped with a 16 5 mL reactor
technical assistance; all central analytical laboratories for their block. Dosing of the solvents as well as sampling (quench and dilution)
support; and Drs. M. Karpf and R. Schmid for helpful discussions. was fully automated. HPLC analyses were performed off-line (the
quench and dilution protocol provided stable samples).
(20) Negative values of the enantiomeric excess indicate that crystal-
’ REFERENCES lization of the (R)-enamine ()-DBTA salt has started, in which case the
(1) http://www.cdc.gov/chronicdisease/resources/publications/AAG/ (R)-enantiomer becomes predominant, and analytical sampling be-
ddt.htm. comes difficult because of the heterogeneous reaction mixture.
(2) http://www.diabetesatlas.org/content/diabetes-and-impaired- (21) Dichloromethane is the only solvent which can be used to
glucose-tolerance. extract the relatively polar unprotected ester.
(3) Gupta, R.; Walunj, S. S.; Tokala, R. K.; Parsa, K. V. L.; Singh, (22) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972,
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R.; Sebokova, E.; Sprecher, U.; Wessel, H. P. Bioorg. Med. Chem. Lett. up because the reactions tend to be exothermic.
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Chem. Lett. 2010, 20, 1109.(c) B€ohringer, M.; Kuhn, B.; L€ubbers, T.; usually remained after the reaction.
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(30) This byproduct is presumably formed by intramolecular trap-
ping of the intermediate isocyanate, followed by intermolecular addition
to a second isocyanate.
(31) During this distillation 29 is quantitatively hydrolyzed to yield
30.
(32) The urea byproduct 30 is carried through to the final step where
it is deprotected. It could not be depleted by crystallization in any step
and hence must be limited to max. 0.25% in isolated amine 10.
(33) 31 was typically produced with 99.099.5% ee. See reference 8
for details.
(34) Openshaw, H. C.; Whittaker, N. J. Chem. Soc. C 1969, 89.
(35) The cyclization was also performed under Mitsunobu condi-
tions using diethyl azodicarboxylate (DEAD), di-tert-butyl azodicarbox-
ylate (DTAD) or diisopropyl azodicarboxylate (DIAD) in combination
with triphenylphosphine or tributylphosphine. However, the crude yield
usually was below 70%, the separation from the phosphine oxides was
difficult, and the cost of the reagents was an issue. This variant was
therefore abandoned in favor of above cheap and effective mesyla-
tioncyclization method. For related cyclizations under Mitsunobu
conditions, see: Bell, I. M.; Beshore, D. C.; Gallicchio, S. N.; Williams,
T. M. Tetrahedron Lett. 2000, 41, 1141.
(36) During workup, silicon-containing byproducts (e.g., hexam-
ethyldisiloxane or trimethylsilanol) are formed, which are present in all
organic and aqueous waste streams and which cause plugging of the
pipes upon incineration if no appropriate incineration facilities are
in place.
(37) Lithium tert-butoxide is commercially available as a 20% (w/w)
solution in THF from e.g. Chemetall.
(38) If hydroxybutyramide 32 is heated over the weekend in toluene
(10 mL/g hydroxybutyramide) at 105 °C in the presence of 2-hydro-
xypyridine, 20% by area (HPLC) of amine 10 are formed, showing that it
is indeed a reversible reaction.
(39) This catalyst was found to be considerably more active than
2-hydroxypyridine.
(40) The reaction was originally conducted at higher concentration
(10 L/kg amine) and in a full batch mode. However, under such
conditions, the product crashed out already during the heating period,
leading to an extremely thick suspension and crust formation on the
reactor walls. Also, a constant reaction temperature of 85 °C was probed,
leading to an overall considerably lower and incomplete conversion.
(41) The deprotection of 13 with HCl in acetone revealed only
traces of the nongenotoxic aldol condensation products mesityloxide
and isomesityloxide. For discussion, see: Coffey, D. S.; Hawk, M. K. N.;
Pedersen, S. W.; Ghera, S. J.; Marler, P. G.; Dodson, P. N.; Lytle, M. L.
Org. Process Res. Dev. 2004, 8, 945.
(42) Although all distillates are recyclable, recycling of the solvent
was not taken into account.
(43) Typically, yields of 80% were obtained instead of the 85% in the
experiment described herein. This high yield is due to holdup from the
previous batches.