A Practical Synthesis of [(1S,3S)-3-Aminocyclohexyl]methanol
and 2-[(1S,3S)-3-Aminocyclohexyl]propan-2-ol,
Useful Intermediates for the Preparation of Novel mPGES-1
Inhibitors

Daniel P. Walker; Steven E. Heasley; Allison MacInnes; Tizah Anjeh; Hwang-Fun Lu; Yvette M. Fobian; Joe T. Collins; Michael L. Vazquez; Michael K. Mao

doi:10.1055/s-0031-1289884

LETTER

A Practical Synthesis of [(1S,3S)-3-Aminocyclohexyl]methanol and 2-[(1S,3S)-3-Aminocyclohexyl]propan-2-ol, Useful Intermediates for the Preparation of Novel mPGES-1 Inhibitors

Daniel P. Walker*^a, Steven E. Heasley^a, Allison MacInnes^a, Tizah Anjeh^b, Hwang-Fun Lu^a, Yvette M. Fobian^a, Joe T. Collins^a, Michael L. Vazquez^a, Michael K. Mao^b
^a Pfizer Worldwide Medicinal Chemistry, Pfizer, Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA
Fax: +1(860)6860013; e-Mail: daniel.p.walker.pfizer@gmail.com;
^b Pfizer Worldwide Pharmaceutical Sciences, Pfizer, Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA

Abstract

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Abstract

Microsomal prostaglandin E2 synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. During the course of studies aimed at the identification of a suitable mPGES-1 inhibitor for clinical development, a need arose for preparing enantiomerically enriched amino alcohols (S,S)-2 and (S,S)-3. Described herein, a concise synthesis of (S,S)-2 and (S,S)-3 has been developed wherein both amino alcohols are derived from a commercially available, low-cost starting material.

Key words

carbocycles - heterocycles - anti-inflammatory agents - chiral resolution - rearrangement

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References

References and Notes

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<A NAME="RS06711ST-1B">1b</A> Samuelsson B. Morganstern R. Jakobsson P.-J. Pharmacol. Rev. 2007, 59: 207

A full account on the design, synthesis, SAR and in vivo activity of type-1 compounds will be published elsewhere in due course.

<A NAME="RS06711ST-3">3</A> Hu Y. Yu S.-L. Yang Y.-J. Zhu J. Deng J.-G. Chin. J. Chem. 2006, 795

<A NAME="RS06711ST-4">4</A> Trost BM. Kondo Y. Tetrahedron Lett. 1991, 1613

<A NAME="RS06711ST-5">5</A> Murahashi S.-I. Tanigushi Y. Imada Y. Tanigawa Y.
J. Org. Chem. 1989, 54: 3292

Our vendor supplied hundreds of grams of rac-4 for ca. $100/gram with a lead time of 5-7 weeks.

<A NAME="RS06711ST-7">7</A> Bhatt HS. Patel GF. Vekariya NV. Jadav SK. J. Pharm. Res. 2009, 2: 1606.

Analytical data for (S,S)-6: Peak 2; white solid; mp 69-71 ˚C; [α]^²5 _D 0.2 (c = 1.5, MeOH). ^¹H NMR (500 MHz, MeOH-d ₄): δ = 7.26-7.40 (m, 5 H), 5.10 (s, 2 H), 3.77-3.85 (m, 1 H), 3.41 (d, J = 6.4 Hz, 2 H), 1.76-1.83 (m, 1 H), 1.64-1.75 (m, 2 H), 1.53-1.64 (m, 4 H), 1.38-1.45 (m, 1 H), 1.14-1.23 (m, 1 H). ^¹³C NMR (125 MHz, MeOH-d ₄): δ = 158.3, 138.6, 129.6, 129.1, 129.0, 67.37, 67.34, 47.67, 36.37, 34.74, 32.37, 29.34, 21.42. LRMS (ESI): m/z = 264 [M + H]⁺.

Amines 2 and 3 were found to absorb carbon dioxide and darken with age. We found it more convenient to store these amines as the corresponding carbamates, 6 and 13, which were shelf stable for more than a year, and convert them into 2 and 3 on an add-need basis.

Analytical data for (S,S)-2: ^¹H NMR (400 MHz, MeOH-d ₄): δ = 3.43 (d, J = 6.7 Hz, 2 H), 3.02-3.09 (m, 1 H), 1.79-1.90 (m, 1 H), 1.49-1.70 (m, 7 H), 1.19-1.30 (m, 1 H). ^¹³C NMR (100 MHz, MeOH-d ₄): δ = 66.54, 47.42, 35.99, 35.42, 33.33, 28.87, 20.83. LRMS (ESI): m/z = 130.1 [M + H]⁺.

Analytical data for (S,S)-8: 98% ee (analytical chiral HPLC); [α]^²5 _D -6.4 (c = 1.8, MeOH). ^¹H NMR (400 MHz, MeOH-d ₄): δ = 7.78 (br d, J = 7.4 Hz, 1 H), 7.27 (d, J = 8.4 Hz, 1 H), 7.23 (d, J = 1.96 Hz, 1 H), 7.02 (dd, J = 8.2, 1.95 Hz, 1 H), 4.26-4.32 (m, 2 H), 3.96-4.03 (m, 1 H), 3.43 (d, J = 6.6 Hz, 2 H), 3.20 (td, J = 13.3, 3.1 Hz, 2 H), 2.57 (tt, J = 11.3, 3.9 Hz, 1 H), 1.72-1.91 (m, 5 H), 1.63-1.72 (m, 2 H), 1.53-1.62 (m, 4 H), 1.37-1.46 (m, 1 H), 1.17-1.26 (m, 1 H). ^¹³C NMR (100 MHz, MeOH-d ₄): δ = 175.3, 163.2, 147.4, 144.2, 129.4, 120.5, 115.3, 109.5, 65.81, 45.16, 44.80, 44.70, 42.11, 42.06, 35.24, 33.03, 30.79, 28.04, 27.93, 20.17. LRMS (ESI): m/z = 392 [M + H]⁺.

Compound (R,R)-8 (98% ee) was prepared using similar conditions to that described for the preparation of (S,S)-8 except (R,R)-6 (98% ee) was used in place of (S,S)-6.

Data for compound (S,S)-8 (crystals from MeCN) were collected on a Bruker APEX diffractometer at Pfizer Groton laboratories, and all crystallographic calculations were facilitated by the SHELXIL system: C₂₀H₂₆N₃O₃Cl˙MeCN˙H₂O; FW = 450.96; monoclinic; space group P2 (1); unit cell dimensions: a = 5.0339 (3) Å, b = 12.3675 (5) Å, c = 18.4354 (9) Å; volume = 1145.14 (10) Å^³; Z = 2; D_calcd = 1.308 Mg/m^³; absorption coefficient = 1.772 mm^-¹; F(000) = 480; GOF on F2 = 1.029; final R indices [I >2σ(I)]: R ₁ = 0.0393, wR ₂ = 0.1026.

<A NAME="RS06711ST-14">14</A> Wang J. Limburg D. Carter J. Mbalaviele G. Gierse J. Vazquez M. Bioorg. Med. Chem. Lett. 2010, 1604

<A NAME="RS06711ST-15">15</A> Dicarboxylic acid 7 is sold as a mixture of cis- and trans-isomers (cis/trans = ca. 3:1), and is available in bulk quantities from various vendors for $0.60/gram; alternatively, it can be efficiently prepared via catalytic hydrogenation of isophthalic acid, see: Freifelder M. Dunnigan DA. Baker EJ. J. Org. Chem. 1966, 31: 3438

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<A NAME="RS06711ST-18">18</A> Hewgill FR. Jefferies PR. J. Chem. Soc. 1955, 2767

Analytical data for (S,S)-13: clear oil; Peak 2 (98% ee); [α]^²5 _D -10 (c = 1.0, MeOH). ^¹H NMR (500 MHz, MeOH-d ₄): δ = 7.26-7.38 (m, 5 H), 6.92 (br d, J = 6.59 Hz, 1 H), 5.07 (ABq, J _AB = 15.0 Hz, Δν_AB = 12.0 Hz, 2 H), 3.92-3.98 (m,
1 H), 1.91-1.97 (m, 1 H), 1.82 (d, J = 12.7 Hz, 1 H), 1.74 (d, J = 12.9 Hz, 1 H), 1.58-1.64 (m, 1 H), 1.47-1.58 (m, 2 H), 1.43 (tt, J = 13.2, 3.4 Hz, 1 H), 1.27 (td, J = 13.2, 3.5 Hz,
1 H), 1.11 (s, 3 H), 1.10 (s, 3 H), 1.02 (qd, J = 12.3, 3.8 Hz, 1 H). ^¹³C NMR (125 MHz, MeOH-d ₄): δ = 158.4, 138.6, 129.6, 129.1, 129.0, 73.24, 67.37, 43.92, 32.65, 31.35, 28.19, 27.03, 26.93, 25.41, 22.09. LRMS (ESI): m/z = 313.9 [M + Na]⁺.

Analytical data for (S,S)-3: clear oil. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 3.80-4.25 (br s, 2 H), 3.24-3.28 (m, 1 H), 1.65-1.76 (m, 2 H), 1.48-1.61 (m, 3 H), 1.40-1.48 (m, 1 H), 1.34 (tt, J = 13.7, 3.9 Hz, 1 H), 1.18 (td, J = 12.9, 3.5 Hz,
1 H), 1.00 (s, 6 H), 0.89 (qd, J = 12.1, 3.5 Hz, 1 H). LRMS (ESI): m/z = 158.1 [M + H]⁺.

Analytical data for (S,S)-15: white solid; 98% ee (analytical chiral HPLC). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.57 (br d, J = 7.69 Hz, 1 H), 7.39 (s, 1 H), 7.29 (s, 1 H), 4.11-4.15 (m, 2 H), 3.99-4.03 (m, 1 H), 3.92 (s, 1 H), 3.09-3.15 (m, 2 H), 2.53-2.57 (m, 1 H), 2.34 (s, 3 H), 1.71-1.79 (m, 4 H), 1.54-1.64 (m, 3 H), 1.46-1.53 (m, 3 H), 1.26-1.34 (m, 1 H), 1.08-1.15 (m, 1 H), 1.02 (s, 3 H), 1.01 (s, 3 H), 0.87-0.95 (m, 1 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 173.1, 162.4, 147.3, 142.5, 128.1, 126.9, 115.4, 110.8, 70.46, 44.97, 44.08, 42.00, 40.69, 30.89, 29.64, 27.86, 27.76, 27.21, 26.81, 26.49, 20.52, 19.83. LRMS (ESI): m/z = 434 [M + H]⁺.

Compound (R,R)-15 (98% ee) was prepared using similar conditions to that described for the preparation of (S,S)-15 except (R,R)-13 (98% ee) was used in place of (S,S)-13.