Details for Patent: 7,470,791

Title:	Process for the preparation of roflumilast
Abstract:	The invention relates to novel processes for the preparation of high-purity roflumilast.
Inventor(s):	Kohl; Bernhard (Constance, DE), Mueller; Bernd (Constance, DE), Palosch; Walter (Rielasingen, DE)
Assignee:	Nycomed GmbH (Konstanz, DE)
Filing Date:	Mar 08, 2004
Application Number:	10/531,720
Claims:	1. A process for the preparation of roflumilast by reacting an anion of 4-amino-3,5-dichloropyridine (1) ##STR00004## in which A.sup.+ is a potassium cation, with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2), ##STR00005## in which LG is a suitable leaving group selected from a chlorine atom, a bromine atom or a radical of the formula OC(O)-1-4C-alkyl, wherein (a) the molar ratio of the employed anion of 4-amino-3,5-dichloropyridine (1) to the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is at least 1.8 and at most 2.7, (b) the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out in a solvent selected from dimethylformamide or N-methylpyrrolidone, (c) the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 0.degree. C. and the boiling point of the solvent used, and (d) KOtBu is used to prepare the anion of 4-amino-3,5-dichloropyridine (1). 2. The process according to claim 1, wherein the molar ratio of the employed anion of 4-amino-3,5-dichloropyridine (1) to the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is at least 2 and at most 2.5. 3. The process according to claim 1, wherein the molar ratio of the employed anion of 4-amino-3,5-dichloropyridine (1) to the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 2.2. 4. The process according to claim 1, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out in dimethylformamide. 5. The process according to claim 1, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out in N-methylpyrrolidone. 6. The process according to claim 1, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 15.degree. C. and 40.degree. C. 7. The process according to claim 4, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 15.degree. C. and 40.degree. C. 8. The process according to claim 5, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 15.degree. C.and 40.degree. C. 9. The process according to claim 1, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 20.degree. C. and 30.degree. C. 10. The process according to claim 4, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 20.degree. C. and 30.degree. C. 11. The process according to claim 5, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 20.degree. C. and 30.degree. C. 12. The process according to claim 1, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 13. The process according to claim 4, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 14. The process according to claim 5, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 15. The process according to claim 6, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 16. The process according to claim 7, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 17. The process according to claim 8, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 18. The process according to claim 9, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 19. The process according to claim 10, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 20. The process according to claim 11, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 21. The process according to claim 1, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 22. The process according to claim 4, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 23. The process according to claim 5, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 24. The process according to claim 6, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 25. The process according to claim 7, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 26. The process according to claim 8, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 27. The process according to claim 9, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 28. The process according to claim 10, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 29. The process according to claim 11, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 30. The process according to claim 1, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 31. The process according to claim 4, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 32. The process according to claim 5, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 33. The process according to claim 6, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 34. The process according to claim 7, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 35. The process according to claim 8, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 36. The process according to claim 9, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 37. The process according to claim 10, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-40C-alkyl-ester. 38. The process according to claim 11, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 39. The process according to claim 13, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 40. The process according to claim 14, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 41. The process according to claim 16, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 42. The process according to claim 17, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 43. The process according to claim 19, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 44. The process according to claim 20, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 45. The process according to claim 22, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 46. The process according to claim 23, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 47. The process according to claim 25, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 48. The process according to claim 26, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 49. The process according to claim 28, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 50. The process according to claim 29, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 51. The process according to claim 31, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 52. The process according to claim 32, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 53. The process according to claim 34, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 54. The process according to claim 35, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 55. The process according to claim 37, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 56. The process according to claim 38, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 57. The process according to claim 2, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out in dimethylformamide. 58. The process according to claim 2, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out in N-methylpyrrolidone. 59. The process according to claim 2, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 15.degree. C. and 40.degree. C. 60. The process according to claim 57, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 15.degree. C. and 40.degree. C. 61. The process according to claim 58, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 15.degree. C. and 40.degree. C. 62. The process according to claim 2, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 20.degree. C. and 30.degree. C. 63. The process according to claim 57, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 20.degree. C. and 30.degree. C. 64. The process according to claim 58, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 20.degree. C. and 30.degree. C. 65. The process according to claim 2, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 66. The process according to claim 57, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 67. The process according to claim 58, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 68. The process according to claim 59, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 69. The process according to claim 60, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 70. The process according to claim 61, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 71. The process according to claim 62, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 72. The process according to claim 63, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 73. The process according to claim 64, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 74. The process according to claim 2, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2)is 3 -cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 75. The process according to claim 57, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 76. The process according to claim 58, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 77. The process according to claim 59, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 78. The process according to claim 60, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 79. The process according to claim 61, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 80. The process according to claim 62, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 81. The process according to claim 63, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 82. The process according to claim 64, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 83. The process according to claim 2, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 84. The process according to claim 57, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 85. The process according to claim 58, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 86. The process according to claim 59, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 87. The process according to claim 60, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 88. The process according to claim 61, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 89. The process according to claim 62, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 90. The process according to claim 63, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 91. The process according to claim 64, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 92. The process according to claim 66, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 93. The process according to claim 67, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 94. The process according to claim 69, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 95. The process according to claim 70, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 96. The process according to claim 72, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 97. The process according to claim 73, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 98. The process according to claim 75, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 99. The process according to claim 76, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 100. The process according to claim 78, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 101. The process according to claim 79, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 102. The process according to claim 81, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 103. The process according to claim 82, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 104. The process according to claim 84, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 105. The process according to claim 85, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 106. The process according to claim 87, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 107. The process according to claim 88, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 108. The process according to claim 90, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 109. The process according to claim 91, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 110. The process according to claim 3, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out in dimethylformamide. 111. The process according to claim 3, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out in N-methylpyrrol idone. 112. The process according to claim 3, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 15.degree. C.and 40.degree. C. 113. The process according to claim 110, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 15.degree. C. and 40.degree. C. 114. The process according to claim 111, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 15.degree. C. and 40.degree. C. 115. The process according to claim 3, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 20.degree. C. and 30.degree. C. 116. The process according to claim 110, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 20.degree. C. and 30.degree. C. 117. The process according to claim 111, wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 20.degree. C. and 30.degree. C. 118. The process according to claim 3, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 119. The process according to claim 110, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 120. The process according to claim 111, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 121. The process according to claim 112, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 122. The process according to claim 113, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 123. The process according to claim 114, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 124. The process according to claim 115, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 125. The process according to claim 116, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 126. The process according to claim 117, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 127. The process according to claim 3, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 128. The process according to claim 110, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 129. The process according to claim 111, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 130. The process according to claim 112, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 131. The process according to claim 113, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 132. The process according to claim 114, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 133. The process according to claim 115, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 134. The process according to claim 116, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 135. The process according to claim 117, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 136. The process according to claim 3, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2)is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 137. The process according to claim 110, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 138. The process according to claim 111, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 139. The process according to claim 112, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 140. The process according to claim 113, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 141. The process according to claim 114, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 142. The process according to claim 115, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 143. The process according to claim 116, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 144. The process according to claim 117, wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 145. The process according to claim 119, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 146. The process according to claim 120, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 147. The process according to claim 122, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 148. The process according to claim 123, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 149. The process according to claim 125, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 150. The process according to claim 126, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 151. The process according to claim 128, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 152. The process according to claim 129, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 153. The process according to claim 131, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 154. The process according to claim 132, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 155. The process according to claim 134, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 156. The process according to claim 135, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 157. The process according to claim 137, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 158. The process according to claim 138, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 159. The process according to claim 140, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 160. The process according to claim 141, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 161. The process according to claim 143, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume. 162. The process according to claim 144, further comprising the step of recrystallizing the roflumilast in a mixture of isopropanol and water wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume.