An Alternative Scalable Process for the Synthesis of the Key Intermediate of Omarigliptin

Article abstract of DOI:10.1021/acs.oprd.6b00295

An alternative scalable process for the synthesis of the key intermediate of omarigliptin is described. The asymmetric synthesis relies on the initial diastereoselective alkylation and subsequent aluminum-catalyzed substrate-controlled Meerwein-Ponndorf-Verley reduction. A highly regioselective 5-exo-dig iodocyclization followed to afford 11b, which was then subjected to ring-opening cycloetherification to give product 1 with >99:1 dr and >99% ee in 31.2% overall yield in nine steps. This synthetic strategy has been successfully applied for multikilogram scale production.

Full text of DOI:10.1021/acs.oprd.6b00295

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Full Paper
An alternative scalable process for the
synthesis of the key intermediate of omarigliptin
Guodong Sun, Mingjie Wei, Zhonghua Luo, Yongjun Liu, Zhijun Chen, and Zhongqing Wang
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00295 • Publication Date (Web): 23 Nov 2016
Downloaded from http://pubs.acs.org on November 23, 2016
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An alternative scalable process for the synthesis of the key intermediate of
omarigliptin
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Guodong Sun, Mingjie Wei, Zhonghua Luo, Yongjun Liu, Zhijun Chen, Zhongqing Wang*
HEC Research and Development Center, HEC Pharm Group, Dongguan 523871, PR China
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ABSTRACT：
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An alternative scalable process for the synthesis of the key intermediate of omarigliptin is described. The
asymmetric synthesis relies on the initial diastereoselective alkylation and the subsequent aluminumꢀcatalyzed
substrateꢀcontrolled MeerweinꢀPonndorfꢀVerley (MPV) reduction. And a highly regioselective 5ꢀexoꢀdig
iodocyclization was followed to afford 11b which was then subjected to ringꢀopening, cycloetherification to
give the product 1 with >99:1 dr, >99% ee in 31.2% overall yield for nine steps. This synthetic strategy has
been successfully applied on multiꢀkilogram scale production.
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KEY WORDS: omarigliptin, key intermediate, MPV reduction, 5ꢀexoꢀdig iodocyclization, cycloetherification,
βꢀdihydropyranones
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Type 2 diabetes mellitus (T2DM), the most common form of diabetes, is a rapidly growing metabolic
disorder and considered as a major public health issue all over the world. It accounts for more than 95% of all
diabetes cases affecting almost 6% of the overall population.1 The clinical application of dipeptidyl
peptidaseꢀ4 (DPPꢀ4) inhibitors has recently proven to be an effective new therapy for the treatment of T2DM.
Due to the clinical success of DPPꢀ4 inhibitors, there has been a growing recent interest in this area as
exemplified by the newly approved omarigliptin, which is onceꢀaꢀweek rather than onceꢀaꢀday oral agent
compared to existing therapies in DPPꢀ4 inhibitor.2ꢀ6 Thus it is highly desirable to develop an efficient and
readily scalable process for the synthesis of omarigliptin.
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The retrosynthetic analysis of omarigliptin employed in the previously reported methods7, 8 shown in
Scheme 1 possess a similar synthetic strategy which was logically sound in the use of the key intermediate
ketone 1. These methods differ in the choice of either intermediate 27 or 38 as the precursor to the target
molecule 1.
Scheme 1. The reported retrosynthetic analysis of omariglitin.
In recent reports, Xu et. al. 8a developed a Ruꢀcatalyzed cycloisomerization process for the construction of a
dihydropyran ring from 10 and subsequent hydroborationꢀoxidation followed by a Ruꢀcatalyzed oxidation
established the ketone group. The two contiguous stereogenic centers in 10 were established by a Ruꢀcatalyzed
asymmetric dynamic kinetic resolution (DKR) transfer hydrogenation with the racemic αꢀamino ketone 9.
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(Reported Strategy, Scheme 2) Although this process has been operated on commercial manufacture,8b the
drawbacks were obvious due to the use of heavy metals and complex sequential operations. We wish to report
herein a convenient and readily scalable approach to the synthesis of 1 based on the retrosynthetic strategy
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depicted in Scheme 2.
Scheme 2. Retrosynthetic analysis of omariglitin key intermediate 1.
F
F
NHBoc
NHBoc
hydroborationꢀoxidation
F
O
F
O
F
F
F
F
OH
NHBoc
NHBoc
O
Reported Strategy
3
F
F
OH
10
O
NHBoc
NHBoc
ringꢀopening
1
F
F
O
OH
O
X
(X=Br or I)
X
12
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This Work
F
F
F
F
NHBoc
O
NHBoc
OH
O
Reported Strategy
racemic 9
racemic 7
O
10
NH2
X
+
OH
NHBoc
NHBoc
O
O
OH
9
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This Work
It was envisioned that compound 1 could be generated through a cycloetherification of αꢀhaloꢀγ'ꢀhydroxy
ketone 12, which might be prepared via
a
hydrolytic ringꢀopening reaction of
2ꢀ(halomethylene)ꢀtetrahydrofuran 11. And 11 could in turn be obtained from hydroxy terminal alkyne 10 via
a regioselective intramolecular 5ꢀexoꢀdig halocyclization under appropriate reaction conditions. We further
assumed that the second of the two adjacent stereogenic centers in 10 could be established by a
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substrateꢀcontrolled asymmetric MPV reduction of chiral αꢀamino ketone 9, which can be accessed from the
Weinreb amide derived from chiral amino acid 7. And 7 could be assembled from an asymmetric αꢀalkylation
of glycine enolate synthon. This retrosynthetic strategy is envisaged to provide the desired stereoisomer with
excellent stereoselectivity as both the diastereoselective MPV reduction and asymmetric αꢀalkylation of
glycine enolate synthons are well documented.
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Following this line of retrosynthetic reasoning, we set out to introduce the first stereo center by asymmetric
synthesis of the required chiral αꢀamino acid 7. Due to their great importance, the synthesis of chiral αꢀamino
acids has been widely studied, and a wide variety of synthetic methods10 have been developed for their
preparation. Among the various synthetic approaches, the application of asymmetric αꢀalkylation with Ni(II)
complex 4 as chiral auxiliary caught our attention, which often proves to be efficient for both the
stereoselectivity and applicability for large scale synthesis.11(Scheme 3)
Scheme 3. Synthesis of Weinreb amide (S)-tert-butyl
(1-(methoxy(methyl)amino)-1-oxopent-4-yn-2-yl)carbamate 8.
Thus the synthesis of compound 5 was initially explored, which could be achieved by the asymmetric
αꢀalkylation of Ni(II) complex 4 with 13.11b,f Studies on screening of the reaction conditions revealed that the
choice of solvent and temperature seemed to be critical to achieve a reproducible conversion and high
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stereoselectivity for this alkylation (see SI Table 1). Under the optimized conditions, the formation of the
major byproduct epi-5 could be efficiently controlled to less than 1.0% when the reaction was performed in
the presence of sodium hydroxide (NaOH) in N,Nꢀdimethylformamide (DMF) at ꢀ10°C (see SI table 1 entry 4).
The isolation and purification of the desired product 5 was extremely simple and efficient. At the end of the
reaction, water was added to the reaction mixture and the product 5 crystallized out from the aqueous media
containing DMF. On kilo batches, we successfully obtained 5 in 97.8% yield with a purity of 95.8% and epi-5
was below 1.0% by HPLC.
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For the following step, it was worth noting that the use of tetrahydrofuran (THF) as the solvent was
beneficial for the workup. When the reaction was finished, the reaction system separated to two layers and the
lower aqueous phase containing Sꢀpropargylglycine 6 was directly subjected to the Bocꢀprotection to obtain 7,
meanwhile the chiral auxiliary 14 could be recycled from the organic layer as its hydrochloric salt with the
recovery above 90%.11d After acidic workup and extraction with dichloromethane (DCM), the crude 7 was
directly used as a DCM solution for the synthesis of 8 without isolation and further purification.
The subsequent treatment of 7 to 8 by a mixed anhydride method was operated in the presence of ethyl
chloroformate and Nꢀmethylmorpholine in dichloromethane (DCM) below 0°C, which afforded the desired
Weinreb amide 8 in 77% yield with above 98% ee over three steps for the oneꢀpot process (see SI Table S2,
entry 4). However, the conditions reported in previous literatures8 using 1,1'ꢀcarbonyldiimidazole (CDI) as
coupling reagent caused significant racemization (see SI Table S2, entry 1ꢀ3).
Transformation of 8 to αꢀamino ketone 9 was initially attempted using a published procedure8
(1,4ꢀdifluoroꢀ2ꢀbromobenzene with iꢀPrMgCl in THF) and the reaction gave similar yield. However the ee of
9 was found to vary between batches. For the asymmetric DKR transfer hydrogenation it was not necessary to
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control the chiral erasion, but for us it was a challenge that had to be overcome. After a close study, it was
found that the temperature during the quenching was a key factor for the control of the ee. When the
temperature was kept below 10°C, the ee could be maintained at about 99% (see SI Table S3, entry 1ꢀ2),
whereas at up to 30°C, the ee decreased drastically (see SI Table S3, entry 4). Quenching at 60°C resulted in
even a racemate (see SI Table S3, entry 5). To avoid the racemization, the reaction mixture was quenched by 2
M HCl solution at ≤0 °C. The ee kept no change when removing THF under vacuum at 40 °C. The residue
of was slurried in the mixture of isopropanol and nꢀheptane to afford enantiomerically pure 9 with 99.9% ee in
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81.4% yield. (Scheme 4)
Scheme 4. Synthesis of omariglitin key intermediate 1 from amide 8.
Previously, Yin and coꢀworkers developed a practical reduction of protected αꢀaminoketones using a highly
diastereoselective MeerweinꢀPonndorfꢀVerley (MPV) reaction.12a This green process used Al(OiꢀPr)3 as
catalyst and iꢀPrOH as the hydride source, which was suitable for scaleꢀup.12b,c,d Thus 9 was converted to
αꢀaminoalcohol 10 with catalytic amount of Al(OiꢀPr)3 (0.4eq) and iꢀPrOH in dichloromethane (DCM) at
reflux. This substrateꢀcontrolled MPV reduction gave high diastereoselectivity. The reaction might proceed
via the rigid sixꢀmembered cyclic transition state A 12a,e,f through chelation with the deprotonated carbamate as
shown in Scheme 4.
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Having accomplished the preparation of 10, which bears the two desired stereo centers, we turn our focus to
its transformation to βꢀdihydropyranone 1. As described in Scheme 4, we envisioned that the construction of
βꢀdihydropyranone 1 can be accomplished through a halocyclizationꢀringꢀopening—cycloetherification
sequence of acetylenic alcohol 10. To our knowledge, this is the first report to synthesize substituted
βꢀdihydropyranones from terminal hydroxy alkynes by such a synthetic strategy. According to the previous
reports13, the 2ꢀ(halomethylene)tetrahydrofuran derivatives could be easily assembled from hydroxy
substituted terminal alkynes via intramolecular 5ꢀexoꢀdig halocyclization in high yields. In our initial studies,
the bromocyclization of 10 with NBS was tested as the model reaction. Indeed,
2ꢀ(bromomethylene)tetrahydrofuran 11a could be obtained in good yield(81%, Table S4, entry 1). However,
the subsequent cycloetherification of 12a to 1 was found to be very slow (>48h) and hard to convert totally. It
was anticipate that the iodide analog 12b should be more reactive in its conversion to 1. In this event the
5ꢀexoꢀdig iodocyclization of 10 with iodine was thus performed to give enol ether 11b, and the reaction could
be completed within 12h in high yield with excellent diatereoselectivity (see SI, Table S4, entry 2). It was also
found that, when methanol was used as the solvent, 11b directly crystallized out from the reaction system and
could be isolated after simple filtration as a single isomer (Zꢀisomer 13a) with >99:1 dr, ee>99% in 72% yield
over two steps from 9. The content of bisꢀiodide 15b (scheme 4) was less than 5%.
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In the proposed mechanism, this iodocyclization reaction might be carried out in stepwise, acetylenic
alcohol 10 was first converted to 1ꢀiodoalkyne with iodine under alkaline conditions,14 followed by a
5ꢀexoꢀdig cyclization involving a vinylic anion intermediate B which could immediately transfer to the desired
product 11b or bisꢀiodide 15b in the presence of excess I2. (Scheme 5) The absolute configuration of
compound 11b is characterized by single crystal Xꢀray diffraction (see SI Figure S1).
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Scheme 5. Proposed Mechanism.
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Acidic hydrolysis of 11b to form the αꢀiodoꢀγ'ꢀhydroxy ketone 12b appeared to be challenging due to the
presence of the acidꢀsensitive Boc protecting group. Surprisingly, such a simple approach was rarely reported
so far.13b Screening of the acids indicated that sodium bisulfate monohydrate was suitable for this
transformation (See SI table S5 entry 1). However, using stronger acids such as BsOH，TsOH，MsOH or
performing the reaction at higher temperatures lead to partial cleavage of the Boc protecting group (see SI
table S5 entry 2ꢀ4,7ꢀ8). Whereas the use of HCl gave no product but only the Boc deꢀprotected product (see SI
Table S5, entry 5). Under the optimized conditions, the crude 12b was directly subjected to the
cycloetherification without further purification15. The cyclization reaction went to completion in THF in the
presence of Na2CO3 at 65°C. And the crude product 1 was slurried in nꢀheptane to give the pure product
with >99:1 dr and >99% ee in 70.8% overall yield for the last two steps in a one pot process.
Conclusion
In summary, an alternative asymmetric synthesis of the key intermediate of omarigliptin has been developed.
This practical synthesis features not only an application of asymmeric alkylation of glycine and
substrateꢀcontrolled diastereoselective MPV reduction to establish the two contiguous stereogenic centers, but
also a highly regioselective 5ꢀexoꢀdig iodocyclization and the subsequent ringꢀopening, cycloetherification to
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give the product 1 with >99:1 dr, >99% ee in 31.2% overall yield. As the advantage in this process, a heavy
metal free transformation of acetylenic alcohol 10 to βꢀdihydropyranone 1 was developed and has been
successfully applied on multiꢀkilogram scale production. Further optimization to avoid the use of heavy metal
in the whole process is underway in our team.
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Experimental section
Commercially available materials purchased from Alfa Aesar or Kelong were used as received. If no
special indicated, all reagents and solvents were used as commercially available without further purification.
NMR spectra were measured on a Bruker Avance 400 spectrometer or 600 spectrometer in the solvents
1
indicated; chemical shifts are reported in units (ppm) by assigning TMS resonance in the H spectrum as 0.00
ppm, CDCl3 resonance in the 13C spectrum as 77.0 ppm. Coupling constants are reported in Hz with
multiplicities denoted as singlet (s), doublet (d), triplet (t), quartet (q), dd (doublet of doublets); m (multiplets),
and etc. HRMS were performed on Fourier Transform Ion Cyclotron Resonance Mass Spectrometer.
Analytical HPLC for liquid phase was carried out on a Agilent HPLC workstation, equipped with a Agilent
Zorbax Eclipse XBridgeTM C18 (4.6 x 250 mm; 5ꢁm) and OJꢀH chiral chromatograph. Optical rotations were
measured using a 1 mL cell with a 1 dm path length on a Jasco Pꢀ1030 polarimeter and are reported as follows:
[α]2D5 (c in g per 100 mL solvent).
(S)-2-((E)-((2-((S)-1-benzylpyrrolidine-2-carboxamido)-5-chlorophenyl)(phenyl)methylene)amino)pent-
4-ynoic
acid
nickel
complexes
(5).
SꢀNꢀ
(2ꢀ
formylꢀbenzylꢀ4ꢀchlorophenyl)
ꢀ1ꢀbenzylꢀpyrrolidineꢀ2ꢀcarboxamideꢀglycine nickel complexe 4 (2000g, 3.75mol) was added to N, Nꢀ
dimethylformamide (8 L), then the mixture was cooled to ꢀ10oC. Previously prepared 40% sodium hydroxide
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(562g, 5.62mol) aqueous solution was added to the reaction mixture in one portion with vigorous stirring. The
6
7
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mixture was stirred at ꢀ10 C for 0.5 h. Then 3ꢀchloropropyl alkyne 13 (420g, 5.64mol) was added dropwise
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9
o
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over 2h at <0 C. The mixture was stirred at ꢀ10 C for at least 2h until the starting material 4 was <3%
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o
(determined by HPLC). Water (16L) was added slowly over 5h at <10 oC. The slurry was stirred at ꢀ10 C for
2h. Solids were filtered and washed with water until the pH of the filtrate was 7ꢀ8. The wet cake was dried
under vacuum at 60 C to afford 2096g of 5 with 95.8% purity in 97.8% yield. HRMS [M+H]+ for
o
C30H26ClN3NiO3 calculated 570.1089; found 570.1112.
(S)-tert-butyl-(1-(methoxy(methyl)amino)-1-oxopent-4-yn-2-yl)carbamate
(8).
A
mixture
of
(S)ꢀ2ꢀ((E)ꢀ((2ꢀ((S)ꢀ1ꢀbenzylpyrrolidineꢀ2ꢀcarboxamido)ꢀ5ꢀchlorophenyl)(phenyl)methylene)amino)pentꢀ4ꢀyno
ic acid nickel complexe 5 (4000 g, 7mol), water (1640 g), and 36% aqueous hydrochloric solution (3000 g)
o
was added into tetrahydrofuran (16 L). The mixture was stirred at 65 C for at least 3 h until the starting
material 5 was <1% (determined by HPLC). The reaction solution was then cooled to 10 oC. And
ethylenediaminetetraacetic acid disodium salt (3400g, 9.14mol) was added slowly and stirred for 0.5h. The pH
o
was adjusted to 9ꢀ10 with 20% sodium hydroxide aqueous solution at <25 C. The organic phase was
separated, and the aqueous phase was extracted with dichloromethane (8L). The organic layer was discarded.
Boc2O (1.2ꢀ1.3eq) was added slowly into the aqueous layer of 6 at ambient temperature. The aqueous layer
was then basified with 20% sodium hydroxide aqueous solution to pH 9ꢀ10 at ambient temperature every four
hours. The mixture was stirred for 30 h at ambient temperature. Then the aqueous phase was washed with
o
dichloromethane (8L). The organic layer was discarded. The aqueous layer was cooled to 10 C and acidified
with 18% HCl solution to pH 2ꢀ3. Then the aqueous layer was extracted with dichloromethane (12L x 2).
Water of the combined organic layer was removed azeotropically with dichloromethane until moisture content
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was <0.8% and a crude stream of the bocꢀprotected acid 7 was given then. Ethyl chloroformate (759.5g, 7mol)
was added into the above solution of 7 at ꢀ10 oC, then 4ꢀmethylmorpholine (708g, 7mol) was added dropwise
at <0 oC. After the mixture was stirred at ꢀ10 oC for 0.5 h, N,Oꢀdimethylhydroxylamine hydrochloride (682.7g,
7mol) was added in one portion, then another part of 4ꢀmethylmorpholine (708g, 7mol) was added dropwise at
<0 oC. The resulting reaction mixture was stirred at ꢀ10 oC for at least 2h until the rate of 7 was <1% by HPLC
and quenched with water (4.8L). The organic phase was separated, and washed sequentially with saturated
sodium bicarbonate solution (6.4L) and brine (6.4L). The solvent was removed by distillation under reduced
pressure. And the residue was dissolved in isopropyl acetate (10L) and decolorized with activated carbon (640
g), and then the isopropyl acetate was removed in vacuum at 45 oC. Then the nꢀheptane (6L) was added to the
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residue of 8, and cooled slowly to ꢀ5 C. The suspension was stirred at ꢀ5 C for 8 h before filtration. The wet
cake was washed with nꢀheptane (2L) and then dried in vacuum at 30 oC overnight to afford 1380 g of 8 from
1
5 with 98.81% purity and 98.3% ee in 77% yield. H NMR (600 MHz, CDCl3) δ 5.40 (t, J = 36.2 Hz, 1H),
4.79 (s, 1H), 3.75 (s, 3H), 3.19 (d, J = 18.6 Hz, 3H), 2.63 (ddd, J = 39.5, 16.8, 2.8 Hz, 2H), 2.06ꢀ1.95 (m, 1H),
1.42 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 170.73 (s), 155.14 (s), 79.82 (s), 78.90 (s), 71.17 (s), 61.63 (s),
49.05 (s), 32.14 (s), 28.29 (s), 22.62 (s). HRMS [M+Na]+ for C12H20N2O4 calculated 279.1315; found
279.1327. [α]2D5 = ꢀ23.22 (c = 1.0 in MeOH); Melting range: 49 oCꢀ51oC.
(S)-tert-butyl
(1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl)carbamate
(9).
(S)ꢀtertꢀbutylꢀ(1ꢀ(methoxy(methyl)amino)ꢀ1ꢀoxopentꢀ4ꢀynꢀ2ꢀyl)
carbamate
(8)
(1000g,
3.9mol),
1ꢀbromoꢀ2,5ꢀdifluorobenzene (830g, 4.3mol) were added in tetrahydrofurana (5 L) and cooled to ꢀ10 oC. Then
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iꢀPrMgCl solution (2 M in THF, 4875 mL, 9.75mol) was added dropwise into the reaction mixture at <0 C.
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The reaction mixture was stirred for 1 h at ꢀ10 C and warmed to ambient temperature for another 3 h. Then
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the reaction mixture was quenched by 2 M HCl solution at <0 C until the pH was adjusted to 2ꢀ3. The
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separated organic phase was washed with brine (2 x 5 L) and concentrated under vacuum at 40 C. Then
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isopropanol (500 mL) and nꢀheptane (1 L) were added into the residue and heated to 65 C for 0.5h, then
cooled to 30 oC. nꢀheptane (7 L) was added dropwise into the mixture over 1h. And the slurry was then sitrred
at 20 oC for 4 h. Solids were filtered and washed with nꢀheptane (1 L). The wet cake was dried under vacuum
at 40 oC to afford 981.5 g of 9 with 95.8% purity and 99.9% ee in 81.4% yield. 1H NMR (600 MHz, CDCl3) δ
7.64 ꢀ 7.50 (m, 1H), 7.29 ꢀ 7.24 (m, 1H), 7.21 ꢀ 7.06 (m, 1H), 5.70 (d, J = 7.2 Hz, 1H), 5.26 (dd, J = 23.4, 19.6
Hz, 1H), 3.00 ꢀ 2.81 (m, 1H), 2.69 (d, J = 17.2 Hz, 1H), 2.03 (d, J = 26.2 Hz, 1H), 1.47 (d, J = 13.4 Hz, 9H).
13C NMR (151 MHz, CDCl3) δ 193.90 (d, J= 3.8 Hz), 159.62 (s), 157.99 (s), 155.09 (s), 124.42 (d, J= 15.9
Hz), 121.95 (dd, J= 24.6, 9.4 Hz), 118.16 (dd, J= 27.0, 7.9 Hz), 117.33 (dd, J= 25.3, 3.1 Hz), 80.19 (s), 78.17
(s), (s), 71.93 (s), 57.65 (d, J= 8.4 Hz), 28.26 (s), 22.09 (s). HRMS [M+Na]+ for C16H17F2NO3 calculated
332.1069; found 332.1082. [α]2D5 = ꢀ20.07 (c = 1.0 in MeOH); Melting range: 108 oCꢀ110 oC.
tert-butyl ((1R,2S)-1-(2,5-difluorophenyl)-1-hydroxypent-4-yn-2-yl)carbamate (10). (S)ꢀtertꢀbutyl
(1ꢀ(2,5ꢀdifluorophenyl)ꢀ1ꢀoxopentꢀ4ꢀynꢀ2ꢀyl)carbamate (9) (900g, 2.91mol), aluminum isopropoxide (240g,
1.16mol), and isopropanol (900 mL) were added in dichloromethane (9 L). The solution was warmed to 40 oC
and stirred for 12 h. After 9 was <1% (determined by HPLC), the reaction mixture was cooled to 20 oC and the
pH was adjusted to 2ꢀ3 with 1 M HCl solution. The organic phase was washed with 15% aqueous NaOH
solution (4.5 L x 2). The solvent was removed by distillation under reduced pressure at 30 oC to give 10, which
was used for the next step directly. 1H NMR (400 MHz, CDCl3) δ 7.23 (ddd, J = 8.7, 5.5, 3.0 Hz, 1H), 6.95 (pd,
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J = 8.9, 4.3 Hz, 2H), 5.13 (d, J = 4.8 Hz, 1H), 4.95 (s, 1H), 4.01 (s, 1H), 2.58 (ddd, J = 17.1, 6.7, 2.6 Hz, 1H),
2.48 ꢀ 2.33 (m, 1H), 2.02 (t, J = 2.6 Hz, 1H), 1.38 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 160.07 (d, J= 1.9
Hz), 157.66 (d, J= 2.0 Hz), 156.96 (d, J= 2.2 Hz), 130.07 (s), 116.13 (dd, J= 25.1, 8.4 Hz), 115.50 (dd, J= 24.3,
8.7 Hz), 114.85 (dd, J= 25.1, 4.4 Hz), 80.15 (d, J= 12.7 Hz), 76.74, (s)70.92 (s), 69.13 (s), 53.69 (s), 28.13 (s),
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19.98 (s). HRMS [M+Na]+ for C16H19F2NO3 calculated 334.1225; found 334.1244. [α]25 = +35.14 (c = 0.47 in
D
MeOH).
tert-butyl ((2R,3S,Z)-2-(2,5-difluorophenyl)-5-(iodomethylene)tetrahydrofuran-3-yl)carbamate (11b).
o
Methanol (540 mL) was added into 10 obtained from the previous step, and then cooled to 0 C. Potassium
hydroxide (660 g, 11.76 mol) dissolved in methanol (2640 mL) was added to the above solution dropwise at
o
o
<10 C. This mixture was stirrd at 0 C for 0.5h. Then iodine (663 g, 2.61 mol) was added in portions to the
o
reaction solution over 0.5 h. The reaction mixture was stirred at 0 C for another 0.5 h and then warmed to
ambient temperature and stirred for 10 h until 10 was <3% by HPLC. After that water (1.8 L) was added
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dropwise over 1h, and the mixture was cooled to 10 C and stirred for 4h. Later the mixture was filtered and
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washed with water (90 mL). The wet cake was slurried with nꢀheptane (9 L) at 65 C for 0.5 h and then at 10
oC for another 5 h. The slurry was filtered and washed with nꢀheptane (900 mL). The wet cake was dried under
vacuum at 60 oC to afford 914.5 g of 11b with dr>99:1, 99.9% ee, 94.5% purity in 72% yield from 9. 1H NMR
(600 MHz, CDCl3) δ 7.11 ꢀ 6.86 (m, 3H), 5.42 (d, J = 39.0 Hz, 1H), 4.97 (t, J = 17.9 Hz, 1H), 4.85 (s, 1H),
4.35 (s, 1H), 2.94 (dd, J = 16.2, 6.6 Hz, 1H), 2.61 (dd, J = 16.1, 4.0 Hz, 1H), 1.40 (d, J = 27.6 Hz, 9H). 13C
NMR (151 MHz, CDCl3) δ 159.76 (d, J= 2.0 Hz), 159.46 (s), 158.15 (d, J= 2.0 Hz), 154.78 (s), 127.38 (dd, J=
15.9, 7.3 Hz), 116.72 (dd, J= 23.9, 8.5 Hz), 116.35 (dd, J= 24.3, 8.5 Hz), 113.40 (d, J= 27.6 Hz), 82.52 (s),
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80.32 (s), 57.21 (s), 41.72 (s), 35.98 (s), 28.26 (s). HRMS [M+Na]+ for C16H18F2INO3 calculated 460.0192;
found 460.0212. [α]2D5 = ꢀ100.09 (c = 1.0 in MeOH); Melting range: 147 oCꢀ149 oC.
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tert-butyl
((1R,2S)-1-(2,5-difluorophenyl)-1-hydroxy-5-iodo-4-oxopentan-2-yl)carbamate
(12b).
tertꢀbutyl ((2R,3S,Z)ꢀ2ꢀ(2,5ꢀdifluorophenyl)ꢀ5ꢀ(iodomethylene)tetrahydrofuranꢀ3ꢀyl)carbamate (11b) (885.50
g, 2.02 mol) was dissolved in tetrahydrofuran (5.3 L). The sodium bisulfate monohydrate (343.35 g, 2.49 mol)
o
dissolved in water (1.7 L) was added into the reaction mixture above. Then the solution was stirred at 35 C
for 12 h until 11b was <1% by HPLC. The organic phase was separated and washed with brine, then was
concentrated under vacuum at 30 oC to give 12b. And crude 12b was used for next step directly. 1H NMR (600
MHz, CDCl3) δ 7.18 ꢀ 7.10 (m, 1H), 6.98 (dd, J= 9.0, 4.3 Hz, 1H), 6.95 ꢀ 6.92 (m, 1H), 5.44 (d, J= 7.1 Hz, 1H),
5.28 (d, J= 11.0 Hz, 1H), 4.15 (m, 1H), 3.59 (d, J= 10.6 Hz, 1H), 3.54 (d, J= 10.6 Hz, 1H), 2.63 ꢀ 2.53 (m, 1H),
2.22 (d, J= 13.0 Hz, 1H), 1.44 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 158.8 (dd, J=243, 2 Hz), 155.9 (dd,
J=243, 2 Hz), 155.3 (s), 129.59 (dd, J= 15.8, 7.4 Hz), 117.18 (dd, J= 24.3, 8.5 Hz), 116.26 (dd, J= 24.4, 8.6
Hz), 114.0 (d, J=25 Hz), 104.05 (s), 80.98 (s), 80.82 (d, J= 30.8 Hz), 58.88 (s), 42.30 (s), 28.84 (s), 13.21 (s).
HRMS [M+Na]+ for C16H20F2INO4 calculated 478.0297; found 478.0323. [α]25 = +21.98 (c = 1.32 in MeOH).
D
tert-butyl
((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carbamate
(1).
Tetrahydrofuran (7.0 L) and sodium carbonate (260 g, 2.45 mol) was added to 12b obtained from the previous
step. And the reaction mixture was stirred at 65 oC until 12b was <3% by HPLC. Then the mixture was cooled
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to 35 C, and the solvent was removed in vacuum at 35 C. Isopropyl acetate (4.4 L) and water (3.5 L) were
added into the residue. The organic phase was separated and washed with brine (3.5 L x 2). After the solvent
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was removed by distillation under reduced pressure at 35 oC, nꢀheptane (1.3 L) was added into the residue and
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heated to 50 C for 0.5 h. Then the slurry was cooled to 20 C and stirred for 2 h. After that the slurry was
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filtered and washed with nꢀheptane (450 mL). The wet cake was then dried under vacuum at 50 C to afford
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469 g of 1 with dr>99:1, >99.9% ee, 94.12% purity in 70.8% yield from 11. H NMR (600 MHz, CDCl3) δ
7.21 (d, J = 3.3 Hz, 1H), 7.06 ꢀ 6.93 (m, 2H), 4.82 (s, 1H), 4.65 (s, 1H), 4.28 (dd, J = 16.3, 1.6 Hz, 1H),
4.16ꢀ4.00 (m, 2H), 3.09ꢀ2.99 (m, 1H), 2.72 (s, 1H), 1.30 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 205.12(s),
159.54 (d, J= 243.1 Hz), 156.78 (d, J= 244.1 Hz), 154.97 (s), 127.82 (dd, J= 16.0, 7.7 Hz), 117.01 (dd, J= 24.3,
8.8 Hz), 115.42 (s), 115.23 (s), 80.70 (s), 75.61 (s), 75.01 (s), 52.91 (s), 45.31 (s), 28.66 (s). HRMS
[M+Hꢀisobutylene]+ for C16H19F2NO4 calculated 272.0729; found 272.0739. [α]25 = +4.92 (c = 1.0 in MeOH);
D
Melting range: 158 oCꢀ160 oC.
Supporting Information
1H and 13C NMR spectra for all new compounds and Xꢀray structure information for 11b (CIF).
Corresponding Authors
Eꢀmail:wangzhongqing@hecpharm.com.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from Guangdong Inovative and Entrepreneurial Research Team
Program (NO. 201001Y0104742262). We thank Zeping Zhan and Guozhu Liu (both HEC pharm Co., Inc.) for
NMR assistance, Jia Yao (HEC pharm Co., Inc.) for Xꢀray crystallographic analysis, Peili Ma and Wenqing
Huang (both HEC pharm Co., Inc.) for HPLC assistance.
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