Tetrahydrothiopyran-4-one as Five-Carbon Source for Scalable Synthesis of (±)-Tapentadol

Article abstract of DOI:10.1021/acs.oprd.9b00121

The improved process for the synthesis of (±)-tapentadol, the FDA-approved analgesic drug, is achieved from tetrahydrothiopyran-4-one as the five-carbon source.

Full text of DOI:10.1021/acs.oprd.9b00121

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Full Paper
Tetrahydrothiopyran-4-one As Five Carbon
Source for Scalable Synthesis of (±)-Tapentadol
Ramagonolla Kranthikumar, Prathama S. Mainkar, Genji
Sukumar, Rambabu Chegondi, and Srivari Chandrasekhar
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00121 • Publication Date (Web): 26 Jun 2019
Downloaded from http://pubs.acs.org on June 26, 2019
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Tetrahydrothiopyran-4-one as Five Carbon Source for
Scalable Synthesis of (±)-Tapentadol
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Ramagonolla Kranthikumar, Prathama S Mainkar, Genji Sukumar, Rambabu Chegondi
and Srivari Chandrasekhar*
CSIRꢀIndian Institute of Chemical Technology (CSIRꢀIICT)
Department of Oraganic Synthesis and Process Chemistry, Hyderabad 500007, India
Eꢀmail: srivaric@iict.res.in
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RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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ABSTRACT: The improved process for synthesis of (±)ꢀtapentadol, the FDA approved analgesic drug is
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achieved from tetrahydrothiopyranꢀ4ꢀone as the 5ꢀcarbon source.
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KEYWORDS: tapentadol, tetrahydrothiopyranꢀ4ꢀone, analgesic, Grignard addition
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INTRODUCTION
Pain management involves complex biological processes. There are a good numbers of drugs
available in the market for the treatment of this unpleasant feeling. The biological process of pain engage
interactions of emotions, senses and behavior.1
Currently the pain symptoms are treated by many approaches. They are classified into anesthetics, nonꢀ
steroidal antiꢀinflammatory drugs, opioids, antiꢀdepressants and others. Morphine (1a) (fig. 1) is on the
top of the pain treatment in adverse cases.2 However, this is an addictive chemical and also patients can
have withdrawal symptoms once treatment is stopped.
Codeine (1b) (Fig. 1) is also an approved drug, which works by a similar mechanism like morphine and
is less addictive compared to morphine.3 Tramadol (2), which is a synthetic equivalent of codeine, was
introduced as a pain killer in the midꢀ1990s. This works by combining weak µꢀopioid and monoꢀ
aminergically (noradrenaline and serotonin) mediated mechanisms.4 The next generation molecule
discovered was tapentadol (3) by Grünenthal (German pharmaceutical company),5,6 which works as a
dual action analgesic and is used in nociceptive and neuropathic pain. The innovators process involved
classical Grignard chemistry and reduction.7 The total synthesis of tapentadol was recently reviewed.8, 9
Figure 1. Structures of FDA approved analgesic drugs.
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Our group has been engaged in developing practical and scalable synthesis of FDA approved drugs viz,
nebivolol,10a asenapine,10b zafirlukast,10c cephalotaxine,10d galanthamine10e etc. We were intrigued by the
excellent properties of tapentadol which has been approved by FDA, for the relief of moderate to severe
acute pain.11 The detailed literature of tapentadol is mostly in the patented domain. The strategies used by
most researcher depend on an acyclic approach wherein the Grignard addition of 3ꢀbromoanisole onto
ethyl ketone generates diastereomeric mixtures which were carried forward to achieve the target molecule
(scheme 1).7,12
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Scheme 1: Previous and present approaches for synthesis of tapentadol.
The reactions are mostly based on diethyl ketone (3 ꢀ pentanone) or derivatives thereof. 3 ꢀ Pentanone
being a volatile compound, the quantities required are more and recovery of starting material is less. Use
of 4ꢀthiopyranone makes the process more compatible to recover starting material and to reuse it.
We reasoned, the Grignard addition of bromoanisole onto a cyclic ketone, which upon opening of the
cyclic form would be a preferred option for a better diastereo control (scheme 2). It occurred to us that
thiopyranꢀ4ꢀone (available at 3ꢀ5 USD/Kg on bulk pricing) could be the best five carbon equivalent, in
cyclic form, which could be reductively opened after Grignard addition.
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Scheme 2: Retrosynthetic Analysis of Tapentadol.
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O
OH
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desulphurization
OH
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N
N
S
3a
4
Grignard
reaction
O
S
O
S
Mannich reaction
N
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6
The original plan was to introduce the dimethylamino methylene group through asymmetric
desymmetrization which was not very prudent (Table 1). Attempts to use organocatalytic reactions
resulted in good yields with no enantioselectivity. The first step of synthesis, Mannich addition, was
carried out using 37% aqueous formaldehyde and 40% aqueous dimethylamine with 4ꢀthiopyranone 6 to
yield 5a in 76% yield.13 Reaction with Lꢀ proline did not result in the preferential formation of any one
enantiomer, probably due to the catalytic role played by the reagent (dimethylamine). Few other chiral
organocatalysts also had the same outcome (see supporting information). A reaction of 100 g scale with
optimized conditions gave 74 g of 5a in 76% yield along with recovery of the starting material (scheme
3).
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Table 1 Screening for optimal reaction conditionsa
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Standard reaction conditions: [a] The reaction was carried out with 6 (0.5 mmol), aldehyde/dimethylamine (0.25 mmol) in
solvent (0.2 M) at room temperature for 24 h. [b] Crude product yield [brsm]. [c] ee determined by chiral GCMS in case of Lꢀ
proline catalysed reactions [d] reaction was carried out under reflux for 3 h.
Scheme 3: Synthesis of Tapentadol.
To the Mannich adduct 5a, was added Grignard reagent of 3ꢀbromoanisole (prepared from magnesium
turnings and 3ꢀbromoanisole in THF) to generate a single diastereomeric tertiary alcohol 4 in 82% of
crude yield which was used for the next step without purification.14 The next obvious synthetic
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transformation was to deoxygenate the tertiary alcohol in 4. Here, we screened various acids and reducing
agents to eliminate the hydroxyl group without disturbing the adjacent stereocenter (Table 2). Among all
conditions, the best was found to be the conversion of compound 4 in TFA/CH2Cl2 (2:1) solvent in
presence of NaBH4 to realize a mixture of 7 & 8 where 8:2 selectivity was observed with 81% yield.15
After water workup, mixture of 7/8 was subjected to desulphurizationꢀhydrogenation, with Raney Ni and
H2 at atmospheric pressure in oneꢀpot to produce the methoxy tapentadol 9 with 97% diastereoselectivity
(confirmed in the next step) in favor of desired diastereomer. Interestingly, the hydrogenation of double
bond in compound 8 also gave 9 with required antiꢀdiastereoselectivity. The demethylation of 9 was
achieved by refluxing in 48% aqueous HBr to produce the tapentadol 3a in 96% yield which was
confirmed by comparison to a standard using HPLC analysis. Total process for the synthesis of target
molecule was achieved without any column chromatography with overall ~ 37% yield.
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The advantage of the current strategy using ketone 6 was the higher de obtained as compared to previous
routes. The synthetic operation from cheaply available tetrahydrothiopyranꢀ4ꢀone 6 provided an added
advantage of scale up at a lowest cost than the acyclic strategy. The resolution of the desired mixture is
known using Lꢀ(ꢀ)ꢀdibenzoyltartaric acid.16
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Table 2. Optimization Conditions for Dehydroxylation[a]
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Standard reaction conditions: [a] The reaction was carried out with acid (0.8 mmol), reducing agent (3.0 mmol) in CH2Cl2 (0.2
M) at room temperature. [b] Determined by LCMS. [c] Combined crude product yield. [d] 15 equiv. of NaBH4 in 0.2 M of
TFA/CH2Cl2 (2:1) solvent. [e] Reaction was carried out without using solvent and product 8 was observed exclusively.
In conclusion, a straight forward and rapid synthesis of (±)ꢀtapentadol was achieved, with better
diastereoselectivity, from totally different raw materials, which are of commercial relevance.
EXPERIMENTAL SECTION
General information: Unless otherwise noted, all reagents were used as received from commercial
suppliers. CH2Cl2 was dried in the presence of calcium hydride and distilled prior to use. THF was dried
in the presence of sodium metal using benzophenone as indicator and distilled prior to use. Reactions
were monitored using thinꢀlayer chromatography (SiO2). TLC plates were visualized with UV light (254
nm), iodine treatment or using ninhydrin stain. Column chromatography was carried out using silica gel
(60ꢀ120 mesh & 100ꢀ200 mesh) packed in glass columns. NMR spectra were recorded at 300, 400, 500
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MHz (H) and at 75, 101, 126 MHz (C), respectively. Chemical shifts (δ) are reported in ppm, using the
residual solvent peak in CDCl3 (H: δ = 7.26 and C: δ = 77.1 ppm) as internal standard, and coupling
constants (J) are given in Hz. HRMS were recorded using ESIꢀTOF techniques.
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EXPERIMENTAL SECTION
3-((Dimethylamino)methyl)tetrahydro-4H-thiopyran-4-one (5a): Tetrahydrothiopyranꢀ4ꢀone (6)
(100.0 g, 860.7 mmol), formaldehyde (37% aq. Solution, 34.92 mL, 430.3 mmol), dimethylamine (40%
aq. Solution, 53.3 mL, 473 mmol) and DMSO (1.5 L) were added to a 5 L reaction vessel equipped with
a mechanical stirrer for 24 h. After completion, the reaction mixture was extracted three times with ethyl
acetate (1×1.5 L, then 2×1 L). The organic layer was acidified (up to pH 2) using 2N HCl to make it
hydrochloride salt which was extracted into water (2×1.5 L). Evaporation of the organic layer gave 35 g
of starting material which was recovered and reused. Then to that aqueous layer was added 2N NaOH (up
to pH 9) to make it free amine which was extracted into ethyl acetate (3×1 L), concentrated under reduced
pressure to give compound 5a as a brownish oil, 74 g (76% yield based on staring material recovery). 1H
NMR (500 MHz, CDCl3) δ 3.17 (dd, J = 13.4, 4.3 Hz, 1H), 2.91ꢀ2.97 (m, 3H), 2.88 – 2.81 (m, 1H), 2.78
– 2.73 (m, 1H), 2.71 ꢀ 2.66 (m, 2H), 2.43 – 2.37 (m, 1H), 2.21 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
210.0, 58.8, 51.0, 45.8, 43.6, 34.5, 31.1; IR (neat) υmax 2940, 2822, 2771, 1701, 1458, 1262, 1038, 850
cmꢀ1; HRMS (ESI) calcd for C8H16NOS [M+H]+: 174.0953 ; found: 174.0951.
3-((Dimethylamino)methyl)-4-(3-methoxyphenyl)tetrahydro-2H-thiopyran-4-ol (4): To a dry 5 L
fourꢀneck flask provided with a thermometer, a stirrer, a cooling tube and a dropping funnel were charged
activated Mg turnings (12.3 g, 508 mmol) and dry THF (500 mL) followed by drop wise addition of a
THF solution (250 mL) of 3ꢀbromoanisole (41.8 mL, 331 mmol) under nitrogen with stirring, where heat
generation was observed after 10 min. and then it was allowed to cool for 1 h. After the Grignard reagent
was prepared, it was slowly added to the 3ꢀ((dimethylamino)methyl)tetrahydroꢀ4Hꢀthiopyranꢀ4ꢀone (5a)
(44.0 g, 254 mmol) in THF (500 mL) drop wise at 0 °C and the stirring was continued for 12 h at room
temperature. After completion of the reaction, sat. NH4Cl (25 mL) was added to the reaction mixture
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slowly at 0 °C and the product 3ꢀ((dimethylamino)methyl)ꢀ4ꢀ(3ꢀmethoxyphenyl)tetrahydroꢀ2Hꢀ
thiopyranꢀ4ꢀol (4) was obtained by extraction with ethyl acetate (1×1.5 L, then 1×1 L) followed by
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concentration to yield yellow oil (58.2 g, 82 %, a single diastereomer). H NMR (500 MHz, CDCl3) δ
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7.28 – 7.24 (m, 1H), 7.16 – 7.03 (m, 2H), 6.77 (dd, J = 8.1, 1.8 Hz, 1H), 3.82 (s, 3H), 3.53 (t, J = 12.7
Hz, 1H), 3.24 (td, J = 13.6, 2.9 Hz, 1H), 2.47 (dd, J = 14.0, 4.4 Hz, 1H), 2.40 – 2.34 (m, 2H), 2.27 – 2.20
(m, 2H), 2.08 (s, 6H), 2.03 – 1.94 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 159.8, 151.1, 129.4, 117.3,
111.9, 110.8, 76.2, 62.1, 55.4, 47.9, 46.1, 42.7, 29.4, 24.9; IR (neat) υmax 3420, 2923, 2832, 1593, 1471,
1429, 1256, 1042, 925, 756, 698 cmꢀ1; HRMS (ESI) calcd for C15H24NO2S [M+H]+: 282.1528 ; found:
282.1525.
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1-(4-(3-Methoxyphenyl) tetrahydro-2H-thiopyran-3-yl)-N, N-dimethylmethanamine (7):
To a stirred solution of trifluoroacetic acid (150 mL) under inert conditions was added NaBH4 (91 g, 2.4
°
mol) slowly at 0 C followed by addition of a solution of 3ꢀ((dimethylamino)methyl)ꢀ4ꢀ(3ꢀ
methoxyphenyl)tetrahydroꢀ2Hꢀthiopyranꢀ4ꢀol (4) (45.0 g, 160. mmol) in CH2Cl2 (250 mL) to the reaction
at the same temperature. The reaction mixture was allowed to stir for 6 hours at ambient temperature.
After completion, reaction mixture was poured into ice water (600 mL) and to the mixture was added
saturated Na2CO3 solution (up to pH 9). The reaction mixture was extracted with CH2Cl2 (2×200 mL,
then 1×100 mL), organic layer was dried and evaporated to give a mixture of products (7& 8) as light
brown oil, 34.5 g (81%) which was used directly for the next reaction without any further purification.
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Crude H NMR showed olefin proton at δ 6.09 – 6.05 ppm as multiplet revealed minor presence of
compound 8.
3-(3-Methoxyphenyl)-N,N,2-trimethylpentan-1-amine
(9)
:
The
crude
1ꢀ(4ꢀ(3ꢀ
methoxyphenyl)tetrahydroꢀ2Hꢀthiopyranꢀ3ꢀyl)ꢀN,Nꢀdimethylmethanamine (7) (55.0 g, 207 mmol) was
dissolved in 750 mL of MeOH and treated with a suspension of Raney Ni (200 g) in 300 mL of MeOH
and heated to 80 °C in an autoclave with an internal hydrogen pressure of 1 bar for 12 h. The reaction was
monitored by TLC and if necessary another batch of Raney nickel was added. After completion, the
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reaction mixture was allowed to settle and the supernatant was removed via pipette and filtered through
Celite. Additional MeOH (500 mL) was added to the reaction mixture and stirred for 5 min before again
being allowed to settle and the supernatant removed. This process was repeated an additional two times
and the combined filtrates were concentrated to give 3ꢀ(3ꢀmethoxyphenyl)ꢀN,N,2ꢀtrimethylpentanꢀ1ꢀ
amine (9) (38 g, 78 %) as yellow oil with 97% diastereomeric excess (based on LCMS analysis).
1H NMR (500 MHz, CDCl3) δ 7.20 (t, J = 7.8 Hz, 1H), 6.77 – 6.66 (m, 3H), 3.8 (s, 3H), 2.35 – 2.28 (m,
1H), 2.21 (s, 1H), 2.17 (s, 6H), 2.05 – 2.0 (m, 1H), 1.83 – 1.68 (m, 2H), 1.63 – 1.52 (m, 1H), 0.97 (d, J =
6.8 Hz, 3H), 0.72 (t, J = 7.4 Hz, 3H).; 13C NMR (101 MHz, CDCl3) δ 159.5, 146.2, 129.1, 121.1, 114.7,
110.7, 64.9, 55.2, 51.7, 45.9, 36.6, 24.2, 16.1, 12.5.; IR (neat) υmax 3171, 2943, 2825, 1593, 1461, 1250,
1040, 780, 706; HRMS (ESI) calcd for C15H26NO [M+H]+: 236.2014 ; found: 236.2022.
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3-(1-(Dimethylamino)-2-methylpentan-3-yl)phenol (3a): A mixture of 3ꢀ(3ꢀmethoxyphenyl)ꢀN,N,2ꢀ
trimethylpentanꢀ1ꢀamine (9) (51.0 g, 217 mmol) and aqueous hydrobromic acid (48%, 300 mL) was
heated under stirring at 100ꢀ110 °C for 3 h and cooled to room temperature. To the reaction mixture was
added sodium bicarbonate (up to pH 9), resulting mixture was extracted with ethyl acetate (500 mL). The
organic layer was washed with water and dried over anhydrous sodium sulphate and concentrated to give
3ꢀ(1ꢀ(dimethylamino)ꢀ2ꢀmethylpentanꢀ3ꢀyl)phenol (3a) (46 g, 96 %) as a Pale yellow oil. By HPLC
analysis revealed exclusive anti diastereomer.
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NMR data for 3ꢀ(1ꢀ(dimethylamino)ꢀ2ꢀmethylpentanꢀ3ꢀyl)phenol (3a) (anti): H NMR (500 MHz,
CDCl3) δ 7.12 (t, J = 7.8 Hz, 1H), 6.68 – 6.61 (m, 2H), 6.58 (s, 1H), 2.33 – 2.27 (m, 1H), 2.17 (s, 6H),
2.15 – 2.10 (m, 1H), 2.09 – 2.00 (m, 1H), 1.90 – 1.83 (m, 1H), 1.78 – 1.68 (m, 1H), 1.60 – 1.49 (m, 1H),
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0.96 (d, J = 6.7 Hz, 3H), 0.70 (t, J = 7.3 Hz, 3H); C NMR (100 MHz, CDCl3) δ 156.5, 146.1, 129.2,
120.3, 115.8, 113.3, 64.8, 51.5, 45.7, 36.6, 23.9, 16.2, 12.4; IR (neat) υmax 3391, 2958, 2871, 1695, 1464,
1266, 1029, 775; HRMS (ESI) calcd for C14H24NO [M+H]+: 222.1858 ; found: 222.1865.
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NMR data for 3ꢀ(1ꢀ(dimethylamino)ꢀ2ꢀmethylpentanꢀ3ꢀyl)phenol (3b) (syn) (obtained from table 2. entry
1 reaction conditions):
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1H NMR (400 MHz, CDCl3) δ 7.10 (t, J = 7.8 Hz, 1H), 6.65 (dd, J = 8.0, 2.1 Hz, 2H), 6.59 – 6.55 (m,
1H), 2.46 – 2.37 (m, 1H), 2.29 – 2.25 (m, 1H), 2.24 (s, 6H), 2.02 – 1.94 (m, 1H), 1.94 – 1.82 (m, 1H),
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1.78 – 1.58 (m, 2H), 0.80 – 0.71 (m, 6H); C NMR (100 MHz, CDCl3) δ 156.2, 144.6, 128.9, 121.4,
116.0, 113.4, 65.4, 50.7, 45.9, 35.8, 26.8, 15.6, 12.7; IR (neat) υmax 3310, 2951, 2865, 1595, 1465, 1263,
1028, 779 cmꢀ1; HRMS (ESI) calcd for C14H24NO [M+H]+: 222.1858 ; found: 222.1878
Acknowledgement
RK thanks University Grants Commission (UGC), New Delhi for a research fellowship. Authors thank
Council of Scientific and Industrial Research (CSIR)ꢀNew Delhi for financial support as part of XII fiveꢀ
year program project under ORIGIN (CSCꢀ108). We gratefully acknowledge Department of Process
Engineering and Technology Transfer, CSIRꢀIICT for providing facilities during scale up process.
ASSOCIATED CONTENT
Supporting Information
1
13
Copies of H and C spectra for all new compounds; this material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: srivaric@iict.res.in
ORCID
Srivari Chandrasekhar: 0000ꢀ0003ꢀ3695ꢀ4343
Prathama S Mainkar: 0000ꢀ0002ꢀ2696ꢀ3759
Rambabu Chegondi: 0000ꢀ0003ꢀ2072ꢀ7429
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CSIR-IICT Manuscript Communication Number: IICT/Pubs./2019/087
Notes
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The authors declare no competing financial interest.
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