Development of a Practical Process for the Synthesis of PDE4 Inhibitors

Article abstract of DOI:10.1021/acs.oprd.6b00104

A practical, safe, and efficient process for the synthesis of PDE4 (phosphodiesterase type 4) inhibitors represented by 1 and 2 was developed and demonstrated on a multi-kilogram scale. Key aspects of the process include the regioselective synthesis of dihydrothieno[3,2-d]pyrimidine-2,4-diol 9 and the asymmetric sulfur oxidation of intermediate 11.

Full text of DOI:10.1021/acs.oprd.6b00104

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Full Paper
Development of a Practical Process for the Synthesis of PDE4 Inhibitors
Rogelio P Frutos, Thomas G. Tampone, Jason Alan Mulder, Sonia
Rodriguez, Nathan Yee, Bing-Shiou Yang, and Chris H. Senanayake
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00104 • Publication Date (Web): 28 Apr 2016
Downloaded from http://pubs.acs.org on May 1, 2016
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Development of a Practical Process for the Synthesis of PDE4 Inhibitors
Rogelio P. Frutos,* Thomas G. Tampone, Jason A. Mulder, Sonia Rodriguez, Nathan K. Yee, Bingꢀ
Shiou Yang and Chris H. Senanayake
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Chemical Development US, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road/P.O.
Box 368, Ridgefield, Connecticut 06877-0368, United States
*
Corresponding Author:
rogelio.frutos@boehringerꢀingelheim.com
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Abstract: A practical, safe and efficient process for the synthesis of PDE4 (phosphodiesterase type 4)
inhibitors represented by 1 and 2 was developed and demonstrated on a multikilogram scale. Key
aspects of the process include the regioselective synthesis of dihydrothieno[3,2ꢀd]pyrimidineꢀ2,4ꢀdiol
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and the asymmetric sulfur oxidation of intermediate 11.
Figure 1. PDE4 Inhibitors 1 and 2
The use of PDE4 (phosphodiesterase type 4) inhibitors for the treatment of COPD (Chronic
Obstructive Pulmonary Disease) by reducing inflammation and improving lung function is well
1,2,3
documented.
Given the potential therapeutic benefit offered by these compounds, a number of
PDE4ꢀselective inhibitors containing a dihydrothieno[3,2ꢀd]pyrimidine core were identified as preꢀ
4
a
clinical candidates in our Discovery laboratories. The continued profiling and evaluation of these
compounds as potential therapeutic agents inevitably necessitated the synthesis of increasingly larger
quantities in a safe, costꢀeffective and practical manner which could not be accommodated using the
4
aꢀc
initial synthetic route.
these compounds.
Herein we describe the development of a practical and scalable approach to
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Scheme 1. Retrosynthetic analysis for 1 and 2
The general approach to PDE4 inhibitors 1 and 2 is shown in Scheme 1 and the first challenge for the
development of an efficient synthesis process was the preparation of intermediate 5. The existing
process for the synthesis of 5 from 4 (See Eq. 1) had to be significantly modified to obtain a reliable,
high yielding and regioselective process. Intermediate 4 was obtained from methyl thioglycolate (3)
5
and methyl acrylate according to a modified literature procedure. Initially, 5 was obtained from 4
under strongly basic conditions (sodium hydride, DME) at low temperature (ꢀ40 °C) resulting in the
desired product along with varying amounts of the undesired regioisomer 7. However, the undesired
regioisomer (7) could only be removed by silica gel chromatography or high vacuum distillation (Eq 1)
6
making this approach undesirable for multiꢀkilo scale synthesis. To solve the above limitations, we
evaluated a number of reported literature procedures for the synthesis of similar compounds.
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The selective synthesis of compounds like 5 from halfꢀthiol diesters by controlled Dieckmann type
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condensations under basic conditions (NaH, NaOMe, etc.) had been reported as well as from αꢀ
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diazoketones via rhodium catalyzed insertion. These results suffered the drawbacks of releasing an
7
8
equivalent of ethanethiol or utilizing undesirable diazo compounds, both of which are potential
issues for large scale synthesis. However, as we also observed, the use of ordinary diesters like 4 for
the base promoted Dieckmann condensation is reported to occur without selectivity to afford a mixture
6
,9
10
of difficult to separate regioisomers. Similarly, the TiCl ꢀmediated regioselective formation of 5
4
from 4 in the presence of Et N gave numerous impurities arising from chlorination and
3
dehydrohalogenation as reported by Deshmukh and coworkers. In addition, the workup procedure
resulted in the formation of vast quantities of solids that had to be laboriously removed. Hence, given
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the limitations of the TiCl procedure, alternative Lewis acids (TiCl (O Pr), TiCl (O Pr) , TiCl(O Pr) ,
4
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Ti(O Pr ), etc.), amine bases and workꢀup conditions were evaluated resulting in a robust and practical
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procedure that utilized TiCl (O Pr) and triethylamine to give 5 as a single regioisomer from 4 in 96%
3
yield.
Scheme 2. Early synthesis of pyrimidineꢀ2,4ꢀdiol 9
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The synthesis of pyrimidineꢀ2,4ꢀdiol 9 from 5 was originally carried out through 2ꢀethylthioꢀ
4
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pyrimidinꢀ4ꢀol 8 following the Medicinal Chemistry route shown in Scheme 2.
One key issue with
this approach was the synthesis and hydrolysis of 8; preparation of this intermediate required two
equivalents of the relatively expensive ethylisothiourea hydrobromide 13 as a raw material and the
yield was a modest 60ꢀ70%. In addition, there was significant decomposition of 5 under the basic
reaction conditions that resulted in the formation foulꢀsmelling byproducts. Furthermore, the
hydrolysis of 8 for the subsequent synthesis of 9 resulted in the release of ethanethiol that also caused
a strong unpleasant stench which proved difficult to contain and neutralize.
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To overcome the issues stated above, a new streamlined and costꢀeffective process for the synthesis of
9, in which inexpensive urea was used in place of the much more costly ethylꢀisothiourea
1
2
hydrobromide (13) was developed.
This new process completely eliminated the strong stench
associated with both the synthesis of 8 and the liberation of ethanethiol upon its hydrolysis. In
addition, the overall cost of the drug substance was significantly reduced and the new process (Eq. 2)
provided a stable, easyꢀtoꢀpurify, solid intermediate (6), eliminating the complications associated with
the transport or storage of crude and nonꢀcrystalline 5.
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a,b
The process for the synthesis of 10 from 9 was also streamlined from the existing procedure
by
reducing the amount of POCl from 10 to 2.0 equiv. and by increasing the reaction temperature from
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5 to 105ꢀ110 °C to afford 10 in 88% yield. These changes facilitated the workꢀup, increased the
throughput and improved the inherent safety of the process both by having less reagent to quench and
1
4
giving more control over a notable exotherm present during the reaction The synthesis of 11 was
then accomplished by carrying out an S Ar displacement of the chlorine at C4 of 10 (Eq. 3) with 4ꢀ
N
aminotetrahydropyran. This transformation was not completely regioselective and approximately 15%
of the product resulting from displacement of the chlorine at C2 was observed. Investigation of
alternative bases (diisopropylethylamine, DABCO, Nꢀmethylpyrrolidine, etc.) and solvents (DMSO,
acetonitrile, isopropanol, water as a coꢀsolvent, etc.) failed to improve the regioselectivity, however,
the undesired regioisomer was significantly more soluble than 11 and was completely removed from
the product during the isolation by filtration. As a result, 11 was obtained in approximately 82ꢀ85%
isolated yield as a single regioisomer.
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The synthesis of 12 (Eq. 4) was accomplished by a modified version of the previous Discovery
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procedure which in turn was based on a general procedure for the asymmetric oxidation of sulfides
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reported by Uemura and coworkers. Key improvements over earlier protocols include an increase in
concentration/throughput, a reduction of the catalyst loading, replacement of the solvent from
chloroform or carbon tetrachloride to dichloromethane and streamlining of the isolation procedure. In
the current protocol the product is isolated as a crystalline solid by filtration following a solvent switch
from dichloromethane to isopropanol upon completion of the reaction. The above modifications
resulted in a streamlined, practical and scalable procedure that provided 12 in good yield (80ꢀ90%)
and excellent enantioselectivity (>99%).
In an attempt to improve the regioselectivity of the S Ar addition, an alternative approach to 12 in
N
which the asymmetric oxidation was carried out on 10 first, followed by the S Ar reaction on the
N
resulting product 14 was also investigated. Although the yield for both transformations (Eq. 5) was
comparable to the previous approach to 12 (Eq. 3 and 4), and the selectivity of the S Ar reaction
N
improved modestly (91:8 vs. 85:15 diastereomeric ratio), intermediate 14 was obtained with a low 70%
ee and this approach was abandoned.
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Once a robust and scalable approach to 12 was identified, we focused our attention on the synthesis of
1
via the addition of the 2ꢀ(piperazinꢀ1ꢀyl)benzo[d]oxazole building block (17) to 12. Accordingly,
the synthesis of 17 was carried out from piperazine 15 and commercially available 2ꢀchloroꢀ
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benzoxazole 16 using a modification of the procedure reported by Sato and coworkers with
1
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optimized reaction conditions (Eq. 6). To complete the synthesis of 1, a suitable procedure was
identified and implemented to couple 11 to 17 under basic conditions affording the desired product in
85ꢀ90% yield (Eq. 7).
The development of a final crystallization process for 1 was carried out next. Identification of a
crystallization process to obtain a proper crystal form is extremely important and oftentimes very
challenging during the development phase of an API (Active Pharmaceutical Ingredient). Accordingly,
extensive solvent screening studies were carried out for 1 until a solvent system consisting of acetic
acid and water was found to reproducibly and exclusively provide a suitable and stable polymorph.
The acetic acid/water crystallization process was then successfully implemented on multiꢀkilogram
scale to provide the desired polymorph of 1 in 80ꢀ85% yield.
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As in the case of 1, once a process for the synthesis of 12 became available we turned our attention to
the synthesis of the 4ꢀ(4ꢀchlorophenoxy)piperidine moiety (21) to complete the synthesis of 2. Initially,
21 was prepared in a twoꢀstep modified literature procedure consisting of an S Ar coupling of 18 and
N
1
8
1
9 followed by BOCꢀdeprotection to give 21 in 75ꢀ77% yield (Eq. 8). Later, a more streamlined
atomꢀeconomic and inexpensive Oꢀselective S Ar procedure was developed (Eq. 9) with unprotected
N
piperidinꢀ4ꢀol (22) that gave 21 in 83ꢀ86% yield.
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The synthesis of 2 was then completed by the S Ar coupling of 12 and 21 under mild basic conditions
N
followed by crystallization of the crude API from ethanol/water to give the product in 83ꢀ86% yield
(Eq. 10).
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In conclusion, a practical, safe and efficient process for the synthesis of PDE4 inhibitors 1 and 2 was
developed and demonstrated on a multikilogram scale that allowed for the efficient preparation of the
desired APIs to support clinical development activities. Key aspects of the process are the
regioselective synthesis of dihydrothieno[3,2ꢀd]pyrimidineꢀ2,4ꢀdiol 9 and the asymmetric sulfur
oxidation of intermediate 11. In addition, the unanticipated efficient synthesis of 21 from unprotected
22 resulted in a more streamlined and cost effective process for 2.
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Experimental section:
Unless otherwise specified, all reactions were carried out in ovenꢀdried glassware under an atmosphere
of nitrogen. NMR spectra were recorded on a 400 MHz NMR spectrometer. Chemical Shifts are
reported in ppm relative to tetramethylsilane; coupling constants (J) are reported in hertz, referred to
as apparent peak multiplicities, and may not necessarily reflect true coupling constants. High
resolution mass spectral data was acquired using a LC/MSD TOF (timeꢀofꢀflight) mass spectrometer
in an electrospray positive ionization mode via flow injection. The commercially available starting
materials were used as received without further purification and all solvents were dried by standard
methods prior to use.
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w
Methyl 3-((2-methoxy-2-oxoethyl)thio)propanoate (4): Methyl thioglycolate (11.0 kg, 95% / ,
w
98.4 mol) and piperidine (167 g, 1.96 mol) were charged under nitrogen into a jacketed reactor with
mechanical stirring. Methyl acrylate (9.42 kg, 111 mol) was then slowly charged over 30 min keeping
the internal temperature at approximately 45 °C. The resulting mixture was stirred at 45 °C for 1 h,
piperidine (674 g, 7.92 mol) was charged and the mixture was then stirred for an additional 30 min.
The mixture was cooled to 15 °C and MTBE (9.4 L) followed by 5% aqueous HCl (9.43 kg, 12.9 mol)
were charged keeping the internal temperature at approximately 15 °C. The organic layer (bottom
layer) was collected, washed with water (9.4 kg) and filtered. The organic portion was charged back
into the reactor and concentrated by distillation at 55 °C to the minimum stirrable volume.
Dichloromethane (9.4 L) was then charged and the resulting mixture was again concentrated to the
minimum stirrable volume by distillation at 40ꢀ45 °C to give 27.2 kg of a 70% solution of 5 in
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dichloromethane (18.9 kg, 99.8% yield) that was used in the subsequent step without additional
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purification. The spectral data of 4 is consistent with literature values.
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Methyl 3-oxotetrahydrothiophene-2-carboxylate (5): Dichloromethane (51.0 L) followed by TiCl4
(10.84 kg, 57.15 mol) were charged under nitrogen into a jacketed reactor equipped with temperature
probe, mechanical stirrer and dropping funnel. The solution was cooled to ꢀ10 °C and isopropanol
(3.36 kg, 55.9 mol) was charged. The mixture was stirred for 30 min and dimethyl 3ꢀthiaadipate 4
(13.63 kg of a 70.0% solution in dichloromethane, 49.6 mol) was charged over 1 hour keeping the
internal temperature at or below ꢀ10 °C. The resulting mixture was stirred for 30 min and
triethylamine (17.42 kg, 172.2 mol) was charged over 1.5 h. The resulting mixture was stirred at or
below ꢀ10 °C for 1.5 and 3N HCl (48.1 kg, 144.3 mol) was slowly charged starting at ꢀ10 ºC and
keeping the internal temperature below 10 °C. The batch was then stirred vigorously at 30 °C for a
minimum of 1 hour. The mixture was allowed to settle, the organic portion was collected and the
aqueous layer was extracted with dichloromethane twice (24 L per extraction). The combined organic
layer was washed with water twice (24 L per wash) and concentrated under reduced pressure by
distillation to give 7.45 kg (95.8 % weight by assay; 44.6 mol) of 5 in 89.8% yield. The spectral data
6,9
of 5 is consistent with literature values.
3-Ureido-4,5-dihydro-thiophene-2-carboxylic acid methyl ester (6): Urea (2.09 kg, 34.8 mol) was
charged into a dry, jacketed reactor equipped with a stirrer, N line and thermocouple thermometer. 3ꢀ
2
oxoꢀtetrahydroꢀthiopheneꢀ2ꢀcarboxylic acid methyl ester 5 (3.0 kg) was charged followed by methanol
(4.5 L). Conc. HCl (290 mL, 3.48 mol) was charged at 20ꢀ25 °C and the mixture stirred at reflux for
1
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ꢀ6 hours. The reaction mixture was cooled to 0 °C and the resulting solid was collected by filtration.
The cake was washed with water twice (2 L water per wash) and dried in a vacuum oven at 50 °C to
1
afford compound 6 as a white solid in 95% yield, H NMR (500 MHz, DMSOꢀd ) δ 3.10 (dd, 2 H, J =
6
0
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13
8
.5, 8.5 Hz), 3.50 (dd, 2 H, J = 8.5, 8.5 Hz), 3.73 (s, 3 H), 6.50ꢀ7.20 (bs, 2 H), 9.47 (s, 1 H); C NMR
(125 MHz, DMSOꢀd ) δ 28.7, 37.8, 52.4, 100.0, 151.6, 154.7, 165.7; LCMS (EI) for C H N O S,
6
7
11
2
3
(M+H)+ calcd. 203.0, measd. 203.0.
6,7-Dihydro-thieno[3,2-d]pyrimidine-2,4-diol (9): 3ꢀUreidoꢀ4,5ꢀdihydroꢀthiopheneꢀ2ꢀcarboxylic
acid methyl ester (6) (2.0 kg, 9.47 mol) was added to a solution of water (6.0 L) and NaOH (379 g,
.47 mol) at ambient temperature. The above mixture was stirred at 85 ºC for 3 hours. After cooling
9
to 0 °C, conc. HCl (861 mL, 10.4 mol) was added slowly until the pH of the solution was 0ꢀ1. The
mixture was cooled to 0 ºC, stirred for 5ꢀ10 min and the resulting solid was collected by filtration.
The cake was washed thoroughly with water twice (1 L per rinse), airꢀdried for 2ꢀ3 hours (suction) and
w
then dried further in a vacuum oven at 50 °C for 12ꢀ16 hours to afford 1.67 kg (92.0% / , 95.0%
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1
yield) of compound 9 as a white solid. H NMR (500 MHz, (DMSOꢀd ) δ 3.11 (dd, 2 H, J = 8.5, 8.5
6
1
3
Hz), 3.31 (dd, 2 H, J = 8.5, 8.5 Hz), 11.14 (s, 1 H), 11.38 (s, 1 H); C NMR (125 MHz, (DMSOꢀd ) δ
6
+
29.3, 35.4, 108.5, 150.5, 152.4, 160.4; LCMS (EI) for C H N O S, (M+H) calcd. 171.0, measd. 171.0.
6
7
2
2
2,4-dichloro-thieno[3,2-d]pyrimidine (10): Solid 6,7ꢀdihydroꢀthieno[3,2ꢀd]pyrimidineꢀ2,4ꢀdiol (9)
(800 g, 4.66 mol) was charged into to an inert and dry jacketed reactor (reactor 1) equipped with a
temperature probe, mechanical stirrer and a dropping funnel. 1.5 L (9.31 mol) of diethylaniline were
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charged over 30 min to 1 h keeping the temperature at or below 25 °C. The internal temperature was
brought up to 105ꢀ110 °C and 0.68 equiv. (868 ml, 34% of the total) of phosphorus oxychloride was
added into the reactor (reactor 1) over 5ꢀ10 min. When the inside temperature began to decrease, the
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internal temperature was maintained at 110 °C and addition of the remaining POCl (1.32 equiv. or 66%
3
of the total) was resumed over a period of 30ꢀ40 min. The internal temperature was adjusted to 105ꢀ
110 °C and the mixture was stirred for 18ꢀ24 h or until complete (HPLC analysis). The mixture was
cooled to 45 °C and THF (400 mL) was charged at 45 °C. The above crude mixture was placed into a
secondary dry reactor (reactor 2). 4.8 L of water were charged into reactor 1 and cooled to 5 °C. The
crude reaction mixture (in reactor 2) was then slowly charged into reactor 1 containing water keeping
the temperature at 5ꢀ10 °C. The mixture was stirred at 5 °C for 30 min to 1 h and the resulting solid
was collected by filtration. The cake was rinsed with water twice (1.6 L per rinse) and the cake was air
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dried in the funnel for 6ꢀ8 h to afford 964 g (92% / ; 88% yield) of crude Compound 10.
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Dichloromethane (4.6 L) was charged into a 10 L reactor. Crude Compound 10 and activated carbon
(46.2 g) were charged into the reactor and the mixture was heated to 40 °C for 20 min. The resulting
solution was collected by filtration through a filter media to remove charcoal. The cake was rinsed
with dichloromethane twice (175 ml per rinse). The solution was concentrated under reduced pressure
to a minimum stirrable volume and the remaining dichloromethane was chased by distillation with a
minimum amount of petroleum ether. Additional petroleum ether (1.3 L) was charged into the reactor
and the mixture was cooled to 10 °C then stirred for 1 h. The resulting solid was collected by filtration
and the cake was rinsed with petroleum ether twice (150 ml per rinse). The cake was air dried in the
funnel (suction) until it appeared dry. The resulting solid Compound 10 was transferred to a suitable
1
tared container and dried in an oven at 50 °C for 6 h to get the final product: H NMR (400 MHz,
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5
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5
6
13
DMSOꢀd ) δ 3.45ꢀ3.56 (m, 4H); C NMR (400 MHz, DMSOꢀd ) δ 29.3, 36.5, 134.8, 151.0, 154.1,
6
6
175.9.
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2-chloro-N-(tetrahydro-2H-pyran-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-amine (11): 2,4ꢀ
Dichloroꢀthieno[3,2ꢀd]pyrimidine (10) (2.62 kg, 12.4 mol), 4ꢀaminotetrahydropyran hydrochloride
(
1.87 kg, 13.6 mol), acetonitrile (13.1 L) and triethylamine (3.76 L, 37.2 mol) were sequentially
charged at ambient temperature into an inert and dry reactor equipped with a temperature probe,
mechanical stirrer, reflux condenser and dropping funnel. The resulting mixture was heated to 70 °C
(reflux) for approximately 20 h. Water (13.1 L) was charged, the mixture was cooled to 5 °C and then
stirred for approximately 1 h. The resulting solid was collected by filtration and the cake was rinsed
twice with a 1:1 solution of acetonitrile/water (2.6 L per rinse) followed by a rinse with acetonitrile
(1.3 L). The cake was dried under vacuum in the filter funnel for approximately 2 h and then dried
w
further in a vacuum oven for 6 h at 50 °C to afford 2.89 kg of product (96.6% / , 82.9% yield) as a
w
1
white solid: H NMR (400 MHz, CDCl ) δ 1.56 (dq, J = 4.8, 11.6 Hz, 2H), 2.02 (br d, J = 11.6 Hz),
3
3.26 (t, J = 8.4 Hz, 2H), 3.42 (t, J = 8.4 Hz, 2H), 3.55 (br t, 11.6 Hz), 4.00 (br d, J = 11.6 Hz, 2H),
13
4
.26 (br, 1H), 4.38 (br, 1H); C NMR (100 MHz, CDCl ) δ 30.7, 33.2, 36.7, 47.2, 66.7, 114.0, 156.6,
3
156.9, 167.9.
(
R)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide
12): (S)ꢀ(ꢀ)ꢀBinaphthol (28.7 g, 98.2 mmol), followed by 11 (2.76 kg, 9.82 mol) were charged to
(
clean, inert and dry reactor equipped with temperature probe, mechanical stirrer and a dropping funnel
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at ambient temperature (20ꢀ25 °C). Next, dichloromethane (15.5 L), titanium (IV) isopropoxide (14.4
g, 49.12 mmol) and purified water (17.69 g, 982.4 mmol) were sequentially charged at ambient
temperature (20ꢀ25 °C) and the mixture was then stirred at 20ꢀ25 °C for 1 h. The jacket temperature
was then adjusted to 10 °C and tertꢀbutyl hydroperoxide solution (70 % aqueous, 1.39 kg, 1.1 equiv.)
was charged slowly while the jacket temperature was adjusted to control the exotherm so as not to
exceed 40 °C or reflux too vigorously. The mixture was then stirred for 2 h while allowing it to cool
to ambient temperature (approx. 20 °C). Heptane (10.2 L) was charged at or below 25 °C and the
mixture was stirred for 1 h at 20ꢀ25 °C. The resulting solid was collected by filtration and cake was
10
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rinsed twice with isopropyl acetate (5.1 L per rinse). The cake was then airꢀdried under vacuum
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(
suction) in the filter funnel for at least 16 h. A 5 % / sodium sulfite solution (248 g, 1.96 mmol)
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was charged to the filtrate and stirred for a minimum of 1 h at approximately 20 °C and stirred until
the peroxide test was negative. The material in the filter was then dried in a vacuum oven for a
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1
minimum of 12 h at 20°C to give 2.83 kg (89.8 % / , 90 % yield) of product as an offꢀwhite solid. H
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NMR (400 MHz, CDCl ) δ 1.49 (dq, J = 4.8, 11.6 Hz, 1H), 1.63 (dq, J = 4.8, 11.6 Hz, 1H), 1.79 (br d,
3
J = 11.6 Hz, 1H), 1.92 (obs m, 1H), 3.21 (m, 2H), 3.51 (m, 2H), 3.96 (br t, J = 11.6 Hz, 2H), 4.32 (m,
13
1H), 6.4 (br, 1H); C NMR (100 MHz, CDCl ) δ 32.1, 32.4, 33.0, 47.6, 50.0, 66.7, 116.7, 159.2,
3
164.1, 173.9.
2-(Piperazin-1-yl)benzo[d]oxazole (17): Piperazine (561 g, 6.45 mol) and dichloromethane (5.0 L)
were charged into an inert and dry jacketed reactor equipped with a temperature probe and mechanical
stirrer. 2ꢀChlorobenzoxazole (500 g, 3.22 mol) was then charged over a period of 1 h keeping the
internal temperature at or below 25 °C. The mixture was stirred for 16 h at ambient temperature and
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the resulting sold (piperazine hydrochloride) was removed by filtration. The filter cake was rinsed
with dichloromethane twice (0.5 L per rinse) and the filtrate was charged back into the reactor. The
solution in the reactor was cooled to 0 °C and water (3.0 L) followed by conc. HCl (0.3 L, 3.60 mol)
was slowly added keeping the temperature at or below 30 °C. The resulting aqueous mixture was
washed with dichloromethane twice (1.9 L per rinse) and cooled once again to 0ꢀ10 °C. 50% NaOH
aqueous solution (0.20 L, 7.58 mol) was charged to bring the pH of the solution to 11ꢀ12 and the
resulting solution was then extracted with dichloromethane twice (1.9 L per rinse). The aqueous layer
was discarded, the organic placed back in the reactor and heptane (1.9 L) was charged. The solution
was concentrated by vacuum distillation to the minimum stirrable volume at 40 °C or below and then
0
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additional heptane (1.9 L) was charged. The resulting solid was collected by filtration and dried in a
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vacuum oven overnight at 50 °C to give 549 g (99.4% / , 88.3% yield) of product as a white solid.
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16
The spectral data of 17 is consistent with literature values.
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4
-(4-Chlorophenoxy)piperidine hydrochloride (21): Potassium tꢀbutoxide (1.37 kg, 95% / , 11.6
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mol), 4ꢀhydroxypiperidine (600 g, 5.81 mol) and Nꢀmethylpyrrolidinone (3.0 L) were charged into an
inert and dry jacketed reactor equipped with a temperature probe, mechanical stirrer and dropping
funnel keeping the internal temperature at or below 35 °C. The temperature was increased to 65 °C
and the mixture as stirred for 0.5 h. 1ꢀChloroꢀ4ꢀfluorobenzene (774 g, 5.81 mol) was charged over a
period of 1 h maintaining the temperature at 65ꢀ75 °C and then the mixture was stirred at 65 °C for 3 h.
The mixture was cooled to ambient temperature and MTBE (6.0 L) followed by water (6.0 L) were
charged. The mixture was stirred for 3ꢀ5 min and then allowed to settle. The organic layer was
collected and the aqueous layer was extracted with MTBE (3.0 L). The combined organic portion was
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washed with water (3.0 L) and concentrated by vacuum distillation at 38ꢀ39 °C to the minimum
stirrable volume. Isopropyl acetate (6.0 L) was charged and a freshly prepared solution of HCl in
isopropyl acetate (3.4 L of a 2.6 M solution) was slowly added keeping the internal temperature at 15ꢀ
10
11
12
13
14
15
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17
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19
20
21
22
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2
5 °C. The mixture was stirred at ambient temperature for 1 h and the resulting solid was collected by
filtration. The cake was rinsed with isopropyl acetate twice (3.0 L per rinse), airꢀdried in the filter
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funnel for 6 h and then dried in a vacuum oven for 6 h at 50 °C to afford 1.24 kg (95.6% / , 83.2%
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1
yield) of product as a white solid. H NMR (400 MHz, DMSOꢀd ) δ 1.86 (m, 2 H), 2.11 (m, 2H), 3.04
6
(m, 2H), 3.19 (m, 2H), 4.66 (m, 1H), 7.04 (d, J = 9.0 Hz, 2H), 7.34 (d, J = 9.0 Hz, 2H), 9.31 (br, 2H);
13
C NMR (100 MHz, DMSOꢀd ) δ 26.9, 40.3, 69.5, 117.6, 124.7, 129.4, 155.4.
6
(R)-2-(4-(benzo[d]oxazol-2-yl)piperazin-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-
dihydrothieno[3,2-d]pyrimidine 5-oxide (1): (R)ꢀ2ꢀchloroꢀ4ꢀ((tetrahydroꢀ2Hꢀpyranꢀ4ꢀyl)amino)ꢀ
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,7ꢀdihydrothieno[3,2ꢀd]pyrimidine 5ꢀoxide (12, 750 g, 88.0% /w, 2.29 mol), 2ꢀ(piperazinꢀ1ꢀ
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yl)benzo[d]oxazole (17, 516 g, 94.8% / , 2.41 mol), tetrahydrofuran (6.00 L) and water (1.50 L)
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were sequentially charged at ambient temperature into an inert jacketed reactor equipped with a
temperature probe, mechanical stirrer and dropping funnel. The mixture was stirred for 30 min,
diisopropylethylamine (444 mL, 2.52 mol) was charged, the mixture was then heated to 65 °C (mild
reflux) and stirred for 4 h. The temperature was brought down to 0 °C, the mixture was stirred for 2 h
and the resulting solid was collected by filtration. The reactor and cake were rinsed sequentially with
a 1:1 mixture of tetrahydrofuran/water (1.50 L) and tetrahydrofuran (0.75 L) and then airꢀdried in the
filter funnel for 2 h. The resulting solid was then dried in a vacuum oven at 50 °C for 12 h to afford
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1.02 kg (95.0% / , 93.0% yield) of crude product as a white solid. The resulting crude material was
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charged back into a reactor followed by a premixed 1 : 0.05 solution of acetic acid (2.40 L) and water
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(
120 mL). The mixture was heated at 35 °C and water (396 mL) was added followed by seed crystals
55.0 g). Additional water (4.50 L) was then charged at a constant rate over a period of 4 h at 35 °C
(
and after completing the water addition the mixture was stirred for an additional 2 h. The resulting
solid was collected by filtration and the cake was rinsed with water three times (4.07 L per rinse) and
0
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2
3
4
5
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7
8
9
0
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2
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9
0
once with acetone (4.07 L). The resulting solid was airꢀdried in the funnel for 1 h and then in a drying
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oven at 80 °C for 12 h to afford 0.93 kg (99.7% / , 96.0 % yield for the crystallization) of product as
w
1
a white solid. H NMR (400 MHz, CDCl ) δ 1.60 (m, 2H), 1.97 (m, 2H), 3.02ꢀ3.09 (m, 2H), 3.35ꢀ3.43
3
(m, 1H), 3.47ꢀ3.54 (m, 2H), 3.57ꢀ3.66 (m, 1H), 3.76 (t, J = 5.2Hz, 4H), 4.01 (m, 4H), 4.16ꢀ4.24 (m,
1
H), 5.73 (d, J = 7.2 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz,
1
3
1
H), 7.38 (d, J = 8.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 33.0, 33.1, 33.3, 43.9, 45.8, 47.7, 50.4,
3
67.1, 108.9, 109.2, 116.9, 121.3, 124.5, 143.3, 149.2, 159.5, 162.4, 163.5. LCMS (EI) for
+
C H N O S, (M+H) calcd. 455.19, measd. 455.32.
22
27
6
3
(R)-2-(4-(4-chlorophenoxy)piperidin-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-
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dihydrothieno[3,2-d]pyrimidine 5-oxide (2): Amine hydrochloride 21 (8.5 kg, 99.9% / , 34.3 mol),
w
w
sulfoxide 12 (10.3 kg, 91.3% / , 32.7 mol), tetrahydrofuran (67.0 L) and water (16.9 L) were charged
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to a mixing tank, heated to 55 °C and passed through a pad of decolorizing charcoal (4.7 kg) into an
inert jacketed reactor equipped with a temperature probe, mechanical stirrer and dropping funnel. The
charcoal pad was then rinsed with a mixture of tetrahydrofuran (15 L) and water (3.8 L) and the rinse
was transferred to the reactor. N,NꢀDiisopropylethylamine (14.2, 81.7 mol) was added keeping the
internal temperature at or below 68 °C. The mixture was then stirred at 68 °C for 3 h and water (132 L)
was charged over a period of 1 h keeping the internal temperature at 68 °C. The mixture was then
cooled to 20ꢀ25 °C linearly over a period of 1 h and stirred for an additional 1 h at this temperature.
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The resulting solid was collected by filtration and then dried in a vacuum oven at 48ꢀ50 °C for 6 h to
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afford 13.1 kg (99.1 / , 86.6 % yield) of crude product as a white solid. The crude material, followed
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by a premixed solution made of ethanol (194 L) and water (17.0 L) were charged into an inert jacketed
reactor equipped with a temperature probe, mechanical stirrer and addition funnel. The mixture was
heated to 60 °C and seed crystals (131 g) were charged. The mixture was stirred at 60 °C and then
cooled linearly to 0 °C over a period of 5 h. The resulting solid was collected by filtration and the
cake was then rinsed with acetone (26.0 L) and dried in a vacuum oven at 60 °C for 12 h to afford 10.6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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1
kg (99.1% / , 80.1% yield from crude material). H NMR (400 MHz, CDCl ) δ 1.49 (dq, J = 4.2,
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3
1
1.8 Hz, 1H), 1.62 (dq, J = 4.2, 11.8 Hz, 1H), 1.74ꢀ1.89 (m, 3H), 1.90ꢀ2.02 (m, 3H), 2.96ꢀ3.07 (m,
H), 3.29 (dt, J = 13.6, 8.4 Hz, 1H), 3.44 (ddd, J = 19.2, 11.2, 2.0 Hz, 2H), 3.62 (dt, J = 17.2, 7.8 Hz,
2
1H), 3.76 (m, 2H), 3.96 (dd, J = 15.6, 12.8 Hz, J = 2H), 4.09ꢀ3.99 (m, 3H), 4.51 (m, 1H), 6.21 (br d, J
13
=
6.0 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H); C NMR (100 MHz, CDCl ) δ 30.4,
3
32.5, 32.7, 41.0, 47.2, 49.6, 66.9, 66.9, 72.9, 107.8, 117.5, 125.9, 129.5, 155.8, 158.9, 163.0, 174.6.
SUPPORTING INFORMATION
1
13
1
H and C NMR spectra of compounds 1, 2, 6, 9, 10, 11, 12, 21 and H NMR spectra for 17.
REFERENCES
1
.
.
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