KW-4490 A PDE4 inhibitor from Kyowa Hakko Kirin

KW-4490 A PDE4 inhibitor from Kyowa Hakko Kirin

FEBRUARY 21, 2014 

KW 4490

cis-4-Cyano-4-(2,3-dihydro-8-methoxy-1,4-benzodioxin-5-yl)cyclohexanecarboxylic Acid 

Cyclohexanecarboxyli​c acid, 4-​cyano-​4-​(2,​3-​dihydro-​8-​methoxy-​1,​4-​benzodioxin-​5-​yl)​-​, cis-

cis-​4-​Cyano-​4-​(2,​3-​dihydro-​8-​methoxy-​1,​4-​benzodioxin-​5-​yl)​cyclohexane-​1-​carboxylic acid;

cis-​4-​Cyano-​4-​(8-​methoxy-​1,​4-​benzodioxan-​5-​yl)​cyclohexanecarboxyli​c acid

KF 66490; KW 4490;

MF C17 H19 N O5

A phosphodiesterase type 4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action ofphosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system

PDE4 hydrolyzes cyclic adenosine monophosphate (cAMP) to inactive adenosine monophosphate (AMP). Inhibition of PDE4 blocks hydrolysis of cAMP, thereby increasing levels of cAMP within cells.

Practical synthesis of the PDE4 inhibitor, KW-4490

ORGN 699

Arata Yanagisawa, arata.yanagisawa@kyowa.co.jp1, Koichiro Nishimura2, Tetsuya Nezu2, Kyoji Ando2, Ayako Maki2, Eiichiro Imai2, and Shin-ichiro Mohri2. (1) Pharmaceutical Research Center, Medicinal Chemistry Research Laboratories, Kyowa Hakko Kogyo Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan, (2) Pharmaceutical Research Center, Sakai Research Laboratories, Kyowa Hakko Kogyo Co., Ltd, 1-1-53 Takasu-cyo, Sakai-ku, Sakai, Osaka, Japan

A practical and scaleable synthesis of the PDE4 inhibitor, KW-4490 (1), was developed for the multi-kilogram preparation. This improved synthesis features construction of the 1-arylcyclohexene by Diels-Alder reaction, followed by a newly established acid-mediated hydrocyanation. The synthesis was achieved in 7 steps in 38% overall yield. Efforts toward increasing the regioselectivity in the Diels-Alder reaction, optimization of crystallization-induced dynamic resolution of the hydrocyanation product, and investigation of other synthetic routes will be presented.

New Reactions and Methodology, Metal-Mediated Reactions, Physical Organic Chemistry, Molecular Recognition and Self-Assembly 7:00 PM-9:00 PM, Wednesday, August 20, 2008 Pennsylvania Convention Center — Blrm A/B, PosterDivision of Organic ChemistryThe 236th ACS National Meeting, Philadelphia, PA, August 17-21, 2008

A team at Kyowa Hakko Kirin in Japan has used a crystallisation-induced dynamic resolution in the synthesis of KW-4490, a PDE-4 inhibitor being developed for asthma and chronic obstructive pulmonary disease.6 Towards the end of the synthesis, they were faced with a mixture of cis and trans diastereomers of an intermediate derived from a hydrocyanation reaction, which was about 62:38 cis:trans; altering the conditions of the reaction did not give a selective process. The desired isomer was the cis, so they wanted to convert the unwanted trans isomer to cis to improve the yield (Scheme 2).

They first tried using a base-induced isomerisation using a base such as potassium t-butoxide, but although this worked to a degree the best ratio of products obtained was 75:25. The same result was obtained when they tested the system on both pure cis and trans isomers, indicating that this ratio represented the thermodynamic equilibrium. However, they realised that the cis isomer was less soluble in ethanol, so they thought the answer might lie in crystallisation-induced dynamic resolution.

They therefore suspended a crude mixture of the two isomers in ethanol and added a catalytic amount of potassium t-butoxide to effect the isomerisation. It was stirred and warmed, and hexane added portion-wise to crash the cis isomer out of solution. The group managed to increase the ratio of isomers to 99:1 by continuous isomerisation, with a 90% isolated yield.

Scheme 2: Kyowa Hakko Kirin found a way to improve the yield of the cis isomer

A Practical Synthesis of the PDE4 Inhibitor, KW-4490

http://pubs.acs.org/doi/abs/10.1021/op1001287?prevSearch=KW%2B4490&searchHistoryKey=

Arata Yanagisawa, Koichiro Nishimura, Kyoji Ando, Tetsuya Nezu, Ayako Maki, Sachiko Kato, Wakako Tamaki, Eiichiro Imai, and Shin-ichiro Mohri

Org. Process Res. Dev., 2010, 14 (5), pp 1182–1187

A practical and scalable synthesis of a PDE4 inhibitor KW-4490 (1) was developed. This improved synthesis features the construction of the 1-arylcyclohexene (9) by the Diels−Alder reaction followed by a newly established Brønsted acid-promoted hydrocyanation. Subsequent crystallization-induced dynamic resolution enabled the high-yield production of the desired cis-isomer (cis-8). The synthesis was achieved in seven steps in 37% overall yield.

Phosphodiesterase 4 (PDE4) is a cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase which is located predominantly in inflammatory cells. High levels of cAMP inhibit the production of cytokines and other molecules that modulate the inflammatory response.(1) Therefore, PDE4 inhibitors have emerged as potential therapeutic agents in the treatment of asthma and chronic obstructive pulmonary disease (COPD).(2) Since cis-4-cyano-4-(2,3-dihydro-8-methoxy-1,4-benzodioxin-5-yl)cyclohexanecarboxylic acid (KW-4490, 1) was identified in Kyowa Hakko Kirin as a potent PDE4 inhibitor,(3) multikilogram quantities were thus required in order to carry out both pharmacological profiling and clinical trials. Structurally, the compound presents the interesting synthetic challenges of constructing a tetra-substituted electron-rich benzene, a tertiary benzylic nitrile, and cis stereochemistry of a carboxylic acid on a 1,4-disubstituted cyclohexane.

In general, tertiary benzylic nitriles has been prepared by the double alkylation of benzylic nitrile,(4) arylations of secondary nitrile anions with aryl halides,(5) or the displacement of tertiary benzylic alcohol with cyanide.(6) The latest approach was applied to our medicinal chemistry synthesis of 1, which was suitable for the delivery of multigram quantities .(3b)

cis-4-Cyano-4-(2,3-dihydro-8-methoxy-1,4-benzodioxin-5-yl)cyclohexanecarboxylic Acid (1)

A mixture of ester cis-8 (20.0 g, 57.9 mmol), ethanol (100 mL), and 6 mol/L KOH (19 mL) was stirred at room temperature for 4 h. The resultant mixture was diluted with water (102 mL), cooled to 5 °C, and neutralized with 6 mol/L HCl. The precipitate was collected by filtration and dried to give crude carboxylic acid 1 (18.2 g, 57.4 mmol). The crude 1 (18.0 g, 56.7 mmol) was dissolved in acetone (170 mL) and water (30 mL) under reflux. The solution was filtered hot and maintaining 55 °C during addition of water (180 mL) to form precipitation. The suspension was cooled to 5 °C, stirred 3 h, and filtered to obtain 1 (17.2 g, cis/trans = >99.99/<0.01, 54.2 mmol, 95% yield) as a white solid: mp 245 °C;

1H NMR (DMSO-d6) δ 12.24 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 4.33−4.23 (m, 4H), 3.75 (s, 3H), 2.36−2.25 (m, 3H), 2.06−1.98 (m, 2H), 1.86−1.64 (m, 4H);

13C NMR (DMSO-d6) δ 175.9, 148.6, 141.9, 133.5, 121.6, 120.5, 116.3, 103.9, 63.7, 63.4, 55.4, 41.0, 38.9, 32.9, 25.6;

IR (KBr) 3288, 2930, 2232, 1730, 1508, 1456, 804 cm−1;

HRMS ESI(−) calcd for C17H18NO5 [M − H]− 316.1185, found 316.1195.

http://pubs.acs.org/doi/suppl/10.1021/op1001287/suppl_file/op1001287_si_001.pdf

……………….

US20040054197

Compound (XIII) is disclosed in WO00/14085 as being useful as a PDE-IV inhibitor. A method for the preparation of a typical compound among compounds (XIII) disclosed in WO00/14085 is as follows:

However, this method is not practically satisfactory as a industrially applicable preparation method, because of (1) requiring multiple steps, (2) low overall yield, (3) requiring purification by silica-gel column chromatography, and the like.

REFERENCE EXAMPLE 1

Synthesis of cis-4-cyano-4-(2,3-dihydro-8-methoxy-1,4-benzodioxine-5-yl)cyclohexanecarboxylic acid

(1) Synthesis of cis-4-cyano-4-(2,3-dihydro-8-methoxy-1,4-benzodioxine-5-yl)cyclohexanecarboxylic acid ethyl ester

Under a nitrogen atmosphere, trifluoromethanesulfonic acid (2.25 g) and trimethylsilylcyanide (1.57 mL) were dissolved in benzotrifluoride (10 mL), and a solution of 4-(2,3-dihydro-8-methoxy-1,4-benzodioxine-5-yl)-3-cyclohexenecarboxylic acid ethyl ester (0.79 g) prepared according to the method described in EXAMPLE 1 in benzotrifluoride (10 mL) was added dropwise at −25° C. After being stirred for for one hour at −20° C., an aqueous saturated sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethanol (1 mL) to give a solid substance (0.64 g). The solid substance (0.030 g) was crystallized from a mixed solvent of diisopropyl ether and ethyl acetate (0.36 mL, diisopropyl ether/ethyl acetate=4/1) to give cis-4-cyano-4-(2,3-dihydro-8-methoxy-1,4-benzodioxine-5-yl)cyclohexanecarboxylic acid ethyl ester (0.019 g, 47.3%) as a solid.

Melting point 131° C.

1H-NMR (CDCl3, δ ppm) 6.84 (d, J=8.9 Hz, 1H), 6.49 (d, J=8.9 Hz, 1H), 4.39−4.33 (m, 4H), 4.17 (q, J=7.1 Hz, 2H), 3.88 (s, 3H), 2.44 (brd, J=12.6 Hz, 2H), 2.32 (tt, J=11.8, 3.8 Hz, 1H), 2.18−1.95 (m, 4H), 1.86 (dt, J=3.6, 12.6 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H).

[0184] IR (KBr, cm−1) 2953, 2228, 1722, 1607, 1504, 1460, 1381, 1325, 1281, 1117, 1043, 953, 787.

MS (m/z) 346(M+H)+.

 (2) Synthesis of cis-4-cyano-4-(2,3-dihydro-8-methoxy-1,4-benzodioxine-5-yl)cyclohexanecarboxylic acid

To a suspension of cis-4-cyano-4-(2,3-dihydro-8-methoxy-1,4-benzodioxine-5-yl)cyclohexanecarboxylic acid ethyl ester (397 g) prepared according to the method described (1) of REFERENCE EXAMPLE 1 in ethanol (1.99 L) was added a 6 ml/L aqueous potassium hydroxide (377 mL), and the mixture was stirred for 4 hours at room temperature. After water (2.03 L) was added to the reaction mixture, a 6 mol/L aqueous hydrochloric acid (576 mL) was added to crystallize and to give cis-4-cyano-4-(2,3-dihydro-8-methoxy-1,4-benzodioxine-5-yl)cyclohexanecarboxylic acid (366 g, 98.1%) as a solid.

Melting point 245° C.

1H-NMR (DMSO-d6, δ ppm) 12.26 (brs, 1H), 6.79 (d, J=8.9 Hz, 1H), 6.59 (d, J=8.9 Hz, 1H), 4.27 (dd, J=11.9, 5.0 Hz, 4H), 3.75 (s, 3H), 2.34−2.26 (m, 3H), 2.05−2.00 (m, 2H), 1.86−1.63 (m, 4H).

IR (KBr, cm−1) 3287, 2932,1728, 1609, 1508, 1454, 1285, 1119, 953, 802, 764.

MS (m/z) 318(M+H)+.

…………………

EP1110961B1

Table 1.

Example 1.
4-Cyano-4-(8-methoxy-1,4-benzodioxan-5-yl) cyclohexanone (Compound 1)(Step A)
Synthesis of 2-(8-methoxy-1,4-benzodioxan-5-yl)acetonitrile (Compound 1a)
• To a solution of 12 g (62 mmol) of 8-methoxy-1,4-benzodioxane-5-carbaldehyde in 140 ml of acetonitrile was added 12 g (110 mmol) of lithium bromide, and then 12 ml (95 mmol) of trimethylsilyl chloride was dropwise added thereto. After 15 minutes, the mixture was ice-cooled, and 19 ml (110 mmol) of 1,1,3,3-tetramethyldisiloxane was dropwise added thereto, followed by stirring at room temperature for 2 hours. The mixture was diluted with methylene chloride, and then was filtered through Celite. The solvent was evaporated in vacuo from the filtrate to give a pale yellow oily substance. To a solution of the obtained crude 5-bromomethyl-8-methoxy-1,4-benzodioxane in 180 ml of DMF was added 9.2 g (190 mmol) of sodium cyanide, followed by stirring at room temperature for 60 hours. To the mixture was added water under ice-cooling, and a solid separated out therefrom was collected by filtration to give 6.8 g (53%) of Compound 1a as an ash-colored solid.
  Melting Point: 121 – 125 °C
  1H-NMR (CDCl3, δ, ppm) 3.60 (s, 2H), 3.88 (s, 3H), 4.33 (s, 4H), 6.50 (d, J = 8 Hz, 1H), 6.86 (d, J = 8 Hz, 1H).
  MASS (m/z) 205 (M+).

(Step B) Synthesis of dimethyl 4-cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)pimelate (Compound 1b)
• To a solution of 6.2 g (30 mmol) of Compound 1a obtained in Step A in 94 ml of acetonitrile were added 1.4 ml (3.0 mmol) of a 40% methanolic solution of Triton B and 27 ml (300 mmol) of methyl acrylate, followed by heating under reflux for 5 hours. The mixture was allowed to stand for cooling, and then poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate = 2/1) to give 6.4 g (56%) of Compound 1b as a pale yellow oily substance.
  1H-NMR (CDCl3, δ, ppm) 2.05-2.37 (m, 4H), 2.39-2.59 (m, 2H), 2.62-2.82 (m, 2H), 3.60 (s, 6H), 3.87 (s, 3H), 4.20-4.40 (m, 4H), 6.48 (d, J = 9 Hz, 1H), 7.01 (d, J = 9 Hz, 1H).
  MASS (m/z) 377 (M+).

(Step C) Synthesis of 4-cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)-2-methoxycarbonylcyclohexanone (Compound 1c)
• To a solution of 6.4 g (17 mmol) of Compound 1b obtained in Step B in 96 ml of 1,2-dimethoxyethane was added 2.0 g (50 mmol) of 60% sodium hydride. After heating under reflux for 3 hours, the mixture was allowed to stand for cooling, poured into ice water, acidified with a 6 mol/liter aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate = 2/1) to give 5.0 g (86%) of Compound 1c as a white solid.
  Melting Point: 129 – 132 °C
  1H-NMR (CDCl3, δ, ppm) 2.21-2.50 (m, 3H), 2.61-2.89 (m, 2H), 3.11(d, J = 15 Hz, 1H), 3.79 (s, 3H), 3.89 (s, 3H), 4.37 (s, 4H), 6.49 (d, J = 9 Hz, 1H), 6.84 (d, J = 9 Hz, 1H), 12.2 (s, 1H).
  MASS (m/z) 345 (M+).

(Step D) Synthesis of Compound 1
• A mixture of 5.0 g (15 mmol) of Compound 1c obtained in Step C, 50 ml of DMSO, 5 ml of water, and 5.0 g of sodium chloride was stirred at 150°C for 5 hours. The mixture was allowed to stand for cooling, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate = 3/1) to give 3.6 g (86%) of Compound 1 as a white solid.
  Melting Point: 157 – 161 °C
  1H-NMR (CDCl3, δ, ppm) 2.21-2.41 (m, 2H), 2.45-2.72 (m, 4H), 2.81-3.00 (m, 2H), 3.89 (s, 3H), 4.37 (s, 4H), 6.51 (d, J = 9 Hz, 1H), 6.88 (d, J = 9 Hz, 1H).
  MASS (m/z) 287 (M+).

Example 2. 4-Cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)cyclohexanone ethyleneketal (Compound 2)
(Step A)Synthesis of 4-hydroxy-4-(8-methoxy-1,4-benzodioxan-5-yl)cyclohexanone ethyleneketal (Compound 2a)
• In 65 ml of THF was dissolved 10 g (41 mmol) of 5-bromo-8-methoxy-1,4-benzodioxane, and 28 ml (45 mmol) of a 1.59 mol/liter solution of n-butyl lithium in hexane was dropwise added thereto at -78°C. After 15 minutes, a solution of 9.6 g (61 mmol) of 1,4-cyclohexadione monoethyleneketal in 50 ml of THF was dropwise added thereto. The mixture was stirred for 1 hour, followed by stirring at room temperature for 20 minutes. Water was added thereto, the mixture was extracted with ethyl acetate, and the extract was washed with brine and dried over sodium sulfate. The solvent was evaporated therefrom, and the residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate = 1/1) to give 9.0 g (68%) of Compound 2a as a white solid.
  Melting Point: 94 – 96 °C
  1H-NMR (CDCl3, δ, ppm) 1.58-1.72 (m, 2H), 1.88-2.28 (m, 6H), 3.57 (s, 1H), 3.86 (s, 3H), 3.90-4.07 (m, 4H), 4.35 (s, 4H), 6.46 (d, J = 9 Hz, 1H), 6.82 (d, J = 9 Hz, 1H).
  MASS (m/z) 322 (M+).
• (Step B) Synthesis of Compound 2
  • In 4.9 ml of methylene chloride was dissolved 0.49 g (1.5 mmol) of Compound 2a obtained in Step A, 0.26 ml (1.9 mmol) of trimethylsilyl cyanide was added thereto at -78°C, then 0.20 ml (1.6 mmol) of a boron trifluoride-ethyl ether complex was dropwise added thereto, and the mixture was stirred for 10 minutes, followed by stirring at room temperature for 10 minutes. A saturated aqueous solution of sodium bicarbonate was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate = 2/1) to give 0.30 g (61%) of Compound 2 as a colorless oily substance.
    1H-NMR (CDCl3, δ, ppm) 1.79-1.95 (m, 2H), 2.06-2.20 (m, 4H), 2.30-2.46 (m, 2H), 3.87 (s, 3H), 3.90-4.07 (m, 4H), 4.36 (s, 4H), 6.48 (d, J = 9 Hz, 1H), 6.82 (d, J = 9 Hz, 1H).
    MASS (m/z) 331 (M+).

Example 3. Compound 1
• In 2.9 ml of acetone was dissolved 0.29 g (0.87 mmol) of Compound 2 obtained in Example 2, 1.2 ml (7.2 mmol) of a 6 mol/liter aqueous hydrochloric acid was added thereto, and the mixture was heated under reflux for 3 hours. The mixture was allowed to stand for cooling and poured into a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate, and the extract was washed with brine. The mixture was dried over sodium sulfate, and the solvent was evaporated to give 0.23 g (92%) of Compound 1 as a white solid.
Example 4. Methyl

cis-4-cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)cyclohexanecarboxylate (Compound 3) and methyltrans-4-cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)cyclohexanecarboxylate (Compound 4)(Step A) Synthesis of 2-[4-cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)cyclohexylidene]-1,3-dithiane (Compound 3a)

• To a solution of 5.0 ml (26 mmol) of 2-trimethylsilyl-1,3-dithiane in 50 ml of THF was added dropwise 17 ml (26 mmol) of a 1.54 mol/liter solution of n-butyl lithium in hexane under ice-cooling. After 10 minutes, the mixture was cooled to -78°C, and a solution of 3.6 g (13 mmol) of Compound 1 obtained in Example 1 in 40 ml of THF was dropwise added thereto. After 10 minutes, to the mixture was added brine, followed by addition of water at room temperature. The mixture was extracted with ethyl acetate, the extract was dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate = 4/1) to give 3.9 g (79%) of Compound 3a as a white solid.
  Melting Point: 164 – 166 °C
  1H-NMR (CDCl3, δ, ppm) 1.70-1.92 (m, 2H), 2.05-2.24 (m, 2H), 2.28-2.53 (m, 4H), 2.89 (t, J = 6 Hz, 4H), 3.18-3.38 (m, 2H), 3.87 (s, 3H), 4.36 (s, 4H), 6.47 (d, J = 9 Hz, 1H), 6.79 (d, J = 9 Hz, 1H).
  MASS (m/z) 389 (M+).

(Step B) Synthesis of Compound 3 and Compound 4
• In 120 ml of methanol was suspended 3.9 g (10 mmol) of Compound 3a obtained in Step A, 1.7 ml (20 mmol) of 70% perchloric acid, and 4.3 g (16 mmol) of mercury chloride (HgCl2) were added thereto, and the mixture was stirred for 4 hours. The mixture was diluted with methylene chloride and was filtered through Celite, the filtrate was poured into a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with methylene chloride. The organic layer was washed with brine and dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate = 1/1) to give the crude Compound 3 as a white solid and also to give 0.18 g (5.5%) of Compound 4 as a colorless transparent oily substance. Compound 3 was further recrystallized from ethyl acetate to give 0.57 g (17%) of white crystals.
  Compound 3
  Melting Point: 123 – 124 °C
  1H-NMR (CDCl3, δ, ppm) 1.75-2.22 (m, 6H), 2.27-2.51 (m, 3H), 3.71 (s, 3H), 3.88 (s, 3H), 4.36 (s, 4H), 6.48 (d, J = 9 Hz, 1H), 6.84 (d, J = 9 Hz, 1H).
  MASS (m/z) 331 (M+).
  Compound 4
  1H-NMR (CDCl3, δ, ppm) 1.92-2.38 (m, 8H), 2.70-2.88 (m, 1H), 3.69 (s, 3H), 3.87 (s, 3H), 4.36 (s, 4H), 6.48 (d, J = 9 Hz, 1H), 6.81 (d, J = 9 Hz, 1H).
  MASS (m/z) 331 (M+).

Example 5.

cis-4-Cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)cyclohexanecarboxylic acid (Compound 5)

• To a mixture of 0.55 g (1.7 mmol) of Compound 3 obtained in Example 4 and 3.3 ml of methanol was added 3.3 ml of THF to dissolve them. To the mixture was dropwise added 2.6 ml of a 1.3 mol/liter aqueous solution of potassium hydroxide, followed by stirring at room temperature for 1 hour. The mixture was poured into water, ethyl acetate was added thereto, and an aqueous layer was extracted. The aqueous layer was acidified with a 1 mol/liter aqueous hydrochloric acid, and the precipitated solid was collected by filtration and re-slurried with ethanol to give 0.45 g (86%) of Compound 5 as a white solid.
  Melting Point: 228 – 230 °C
  1H-NMR (DMSO-d6 , δ, ppm) 1.59-1.90 (m, 4H), 1.94-2.10 (m, 2H), 2.20-2.45 (m, 3H), 3.75 (s, 3H), 4.27 (dd, J = 5, 12 Hz, 4H), 6.60 (d, J = 9 Hz, 1H), 6.79 (d, J = 9 Hz, 1H), 12.2 (br s, 1H).
  MASS (m/z) 317 (M+).
  

  Elemental analysis: C17H19NO5
  Found (%) C	64.09,	H : 6.01,	N : 4.51
  Calcd. (%) C	64.34,	H : 6.03,	N : 4.41

………….

1. Teixeira, M. M.; Gristwood, R. W.; Cooper, N.; Hellewell, P. G. Trends Pharmacol. Sci.1997, 18, 164– 170, [PubMed],
2. Dyke, H. J.; Montana, J. G. Exp. Opin. Investig. Drugs 2002, 11, 1– 13
   
   Lipworth, B. J. Lancet 2005, 365 ( 9454) 167– 175
   
   Kroegel, C.; Foerster, M. Exp. Opin. Investig. Drugs 2007, 16, 109– 124
   
3. Yanagawa, K. The 26th Medicinal Chemistry Symposium, 2007, 2P-29.
   
   Ohshima, E.;Yanagawa, K.; Manabe, H.; Miki, I.; Masuda, Y. PCT Int. Appl. WO0164666 A1, 2001.
   
4. Christensen, S. B.; Guider, A.; Forster, C. J.; Gleason, J. G.; Bender, P. E.; Karpinski, J. M.; DeWolf, W. E., Jr.; Barnette, M. S.; Underwood, D. C.; Griswold, D. E.; Cieslinski, L. B.; Burman, M.; Bochnowicz, S.; Osborn, R. R.; Manning, C. D.; Grous, M.; Hillegas, L. M.; O’Leary-Bartus, J.; Ryan, M. D.; Eggleston, D. S.; Haltiwanger, R. C.; Torphy, T. J. J. Med. Chem. 1998, 41, 821– 835
   
5. Caron, S.; Vazquez, E.; Wojcik, J. M. J. Am. Chem. Soc. 2000, 122, 712– 713
   
   Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234– 245
   
   You, J.; Verkade, J. G. Angew. Chem., Int. Ed. 2003, 42, 5051–5053
   
6. Muratake, H.; Natsume, M. Tetrahedron 1990, 46, 6331– 6342
   
   Caron, S.; Vazquez, E. Org. Process Res. Dev. 2001, 5, 587– 592
   
7. North, M. In Comprehensive Organic Functional Group Transformations; Katritzky, A. R.;Meth-Cohn, O.; Rees, C. W., Eds.; Pergamon: Oxford, 1995; Vol. 3, p 614.
   
8. Lemaire, M.; Doussot, J.; Guy, A. Chem. Lett. 1988, 1581– 1584
   
   Guy, A.; Doussot, J.; Guette, J.-P.; Garreau, R.; Lemaire, M. Synlett 1992, 821– 822
   
   Kurti, L.; Czako, B.; Corey, E. J. Org. Lett. 2008, 10, 5247– 5250
   
9. Yanagisawa, A.; Nezu, T.; Mohri, S. Org. Lett. 2009, 11, 5286– 5289
   
10. Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316– 1319
    
11. Kuivila, H. G.; Nahabedian, K. V. J. Am. Chem. Soc. 1961, 83, 2159– 2163
    
    Kuivila, H. G.; Nahabedian, K. V. J. Am. Chem. Soc. 1961, 83, 2164– 2166
    
    Nahabedian, K. V.; Kuivila, H. G. J. Am. Chem. Soc. 1961, 83, 2167–2174
    
12. Stang, P. J.; Fisk, T. E. Synthesis 1979, 438– 440
    
    Stang, P. J.; Treptow,W. Synthesis 1980, 283– 284
    
    Saulnier, M. G.; Kadow, J. F.; Tun, M. M.; Langley, D. R.; Vyas, D. M. J. Am. Chem. Soc. 1989, 111, 8320– 8321
    
13. Kato, S.; Chujo, I.; Suzuki, K. PCT Int. Appl. WO04000795 A1, 2004.
    
14. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457– 2483
    
    O’Keefe,D. F.; Dannock, M. C.; Marcuccio, S. M. Tetrahedron Lett. 1992, 33, 6679– 6680
    
    Segelstein, B. E.; Bulter, T. W.; Chenard, B. L. J. Org. Chem. 1995, 60, 12– 13
    
    Kong, K.-C.; Cheng, C.-H. J. Am. Chem. Soc. 1991, 113, 6313– 6315
    
15. Brands, K. M. J.; Davies, A. J. Chem. Rev. 2006, 106, 2711– 2733
    
16. Baker, W.; Jukes, E. H. T.; Subrahmanyam, C. A. J. Chem. Soc. 1934, 1681–1684
    Dallacker, F.; Van Wersh, J. Chem. Ber. 1972, 105, 3301–3305
    

•  Yanagisawa, Arata; Organic Process Research & Development 2010, 14(5), P1182-1187 
•  Yanagisawa, Arata; Organic Letters 2009, 11(22), P5286-5289 
• US 20010056117
• WO 2002059105
• WO 2000014085

WO1998022455A1 *	Nov 19, 1997	May 28, 1998	Michio Ichimura	Oxygenic heterocyclic compounds
JP10147585A *				Title not available

WO2001064666A1 *	Mar 2, 2001	Sep 7, 2001	Kyowa Hakko Kogyo Kk	Oxygen-containing heterocyclic compounds
WO2002059105A1 *	Jan 25, 2002	Aug 1, 2002	Kyowa Hakko Kogyo Kk	Styrene derivatives and process for production thereof
WO2006041120A1 *	Oct 13, 2005	Apr 20, 2006	Daisuke Harada	Pharmaceutical composition
WO2006041121A1 *	Oct 13, 2005	Apr 20, 2006	Daisuke Harada	Remedies/preventives for chronic skin disease
WO2006123726A1 *	May 18, 2006	Nov 23, 2006	Daisuke Harada	Pharmaceutical composition
WO2011134468A1	Apr 28, 2011	Nov 3, 2011	Leo Pharma A/S	Biaryl phosphodiesterase inhibitors
EP1362853A1 *	Jan 25, 2002	Nov 19, 2003	Kyowa Hakko Kogyo Co., Ltd	Styrene derivatives and process for production thereof

Share this: