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Details for Patent: 7,470,791

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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.
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