CROSS-REFERENCES TO RELATED APPLICATIONS

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STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

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REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER

PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK

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BACKGROUND OF THE INVENTION

[0004] Phosphodiesterases (PDEs) are a family of enzymes that metabolize 3', 5' cyclic nucleotides to 5' nucleoside monophosphates, thereby terminating cyclic adenosine monophosphate (cAMP) second messenger activity. Phosphodiesterase-4 (PDE4), a high affinity, cAMP-specific type IV PDE, has generated interest as a potential target for the development of novel anti-asthmatic and anti-inflammatory compounds. PDE4 is known to exist in at least four isoforms, each of which is encoded by a distinct gene. Each of the four known PDE4 gene products is believed to play varying roles in over forty allergic and/or inflammatory responses. It is thus believed that the inhibition of PDE4, and in particular the inhibition of specific isoforms that produce detrimental responses, can beneficially affect allergy and inflammation symptoms. Practical and economical methods providing novel PDE4 inhibitors are therefore highly desirable.

[0005] Roflumilast (CAS 162401-32-3) is a member of a class of fluoroalkoxy-substituted benzamides developed by BYK Gulden Lomberg Chemische Fabrik GmbH (see, for example, U.S. Patent No. 5,712,298). The chemical name of roflumilast is 3-(cyclopropylmethoxy)-N- (3,5-dichloro-pyridin-4-yl)-4-(difluoromethoxy)benzamide. The compound is indicated to be useful as a PDE4 inhibitor. [0006] WO 95/01338 describes the preparation of dialkyl- substituted benzamides, including roflumilast, and the use thereof as PDE4 inhibitors. Such compounds are also proposed for the treatment of certain disorders of the skin such as dermatoses. WO

2004/033430 describes the preparation of a dialkoxy-substituted benzoyl compound which can be further converted to dialkoxy-substituted benzamides.

[0007] WO 94/02465 and WO 93/25517 describe the preparation of dialkoxy-substituted benzamides. The compounds are obtained by reacting activated benzoic acid derivatives of the general formula:

with amines of the general formula R ³ H ₂ . The disclosed benzoic acid derivatives are acid halides, especially acid chlorides, and anhydrides. The reaction takes place in the presence of a base (e.g. an organic base such as triethylamine, N-methylmorpholine, or pyridine; or an alkali metal hydride, such as sodium hydride) in an inert solvent.

[0008] WO 2004/080967 describes the preparation of dialkoxy-substituted benzamides from dialkoxy-substituted benzoic acid and the anion of 4-amino-3,5-dichloropyridine.

Roflumilast is prepared using the anion of 4-amino-3,5-dichloropyridine (Scheme 1, Formula 1, below) and an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid that contains a suitable leaving group (Scheme 1, Formula 2, below). The use of a strong base, such as KO ^l Bu, NaO ^l Bu, or LiO ^l Bu, is necessary to prepare the anion 1. The reaction temperature must be maintained between 15 and 30°C. The preparation of benzoic acid derivative 2, where LG is a chloride leaving group, requires 1-4 equivalents of thionyl chloride for reaction with 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl acid at 70-90°C. The coupling of 1 and 2 is carried out at 20-30°C in DMF.

Scheme 1

[0009] WO 2004/033430 describes the preparation of a dialkoxy-substituted benzoyl compound which can be further converted to dialkoxy-substituted benzamides, including roflumilast, using carbonylation technology. The key intermediates, including 3-cyclopropyl methoxy-4-difluoromethoxybenzoic acid and its derivatives (as disclosed in WO

2004/080967), are derived via carbonylation of l-halo-3-cyclopropylmethoxy-4- difluoromethoxyb enzene . [0010] Although processes for roflumilast preparation have been disclosed as discussed above, none of the known methods are environmentally friendly. The known processes are either environmentally unfriendly or use harsh conditions. WO 95/01338, for example, describes the preparation of dialkyl-substituted benzamides using thionyl chloride, reaction of which can produce dangerous gases, and pyrophoric strong bases such as sodium hydride. Meanwhile, WO 2004/080967 describes the preparation of roflumilast using combustible potassium tert-butoxide (KO ^l Bu). Therefore, there is still an unmet need for a simple and safe process for industrial preparation of roflumilast and similar benzamides. The practical and economical processes disclosed herein address this need and other needs.

BRIEF SUMMARY OF THE INVENTION

[0011] In one aspect, the present invention provides a process for the preparation of a compound of formula Vic:

Vic

The process includes: a) converting a compound of formula He

lie

to a compound of formula Vc

Vc

in a one-pot reaction; and

b) oxidizing the compound of formula Vc under conditions suitable to provide the compound of formula Vic;

wherein

R ¹ and R ² are independently selected from the group consisting of H; C _1-6 alkyl; C3-7 cycloalkyl; C3-7 cycloalkylmethyl; and C _1-4 alkyl which is partially or completely substituted with fluorine.

[0012] In a second aspect, the present invention provides a compound of formula Vc

Vc

wherein the 'crossed' imine bond indicates cis, trans or a mixture of cis and trans isomers, as well as a compound of formula IIIc

lllc wherein:

R ¹ are R ² independently selected from the group consisting of H; C _1-6 alkyl; C3-7

cycloalkyl; C3-7 cycloalkylmethyl; and C _1-4 alkyl which is partially or completely substituted with fluorine; and

R ⁴ and R ⁵ are independently selected from the group consisting of C _1-6 alkyl and acyl;

R ⁴ and R ⁵ are taken together to form an optionally substituted 5-7 member cyclic ring. [0013] In a third aspect, the present invention provides a process for the preparation of a compound of structure Vic

Vic

The process includes: a) contacting a compound of formula lie

lie

with a compound of formula IVa

IVa

under conditions sufficient to provide a compound of formula V

V ^c ; and

b) oxidizing the compound of formula Vc under conditions suitable to provide the compound of formula Vic;

wherein

R ¹ are R ² independently selected from the group consisting of H; C _1-6 alkyl; C3-7

cycloalkyl; C3-7 cycloalkylmethyl; and C _1-4 alkyl which is partially or completely substituted with fluorine. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 shows the schematic for the synthesis ofN-(3,5-dichloro-pyridin-4-yl)-3,4- dimethoxy-benzamide from 3,4-dimethoxybenzaldehyde.

[0015] Figure 2 shows the schematic for the synthesis of roflumilast from 3-cyclopropyl methoxy-4-difluoromethoxybenzaldehyde.

DETAILED DESCRIPTION OF THE INVENTION I. General

[0016] The present invention provides a process for preparation of substituted benzamides from substituted benzaldehydes. The novel one-pot methods have been discovered to be mild, safe, economically efficient, and environmentally friendly. The inventive process eliminates the need for caustic or dangerous reagents such as thionyl chloride and sodium hydride.

II. Definitions

[0017] As used herein, the term "contacting" refers to the process of bringing into contact at least two distinct species such that they can react. It should be appreciated, however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0018] As used herein, the term "alkyl" by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical. Alkyl substituents, as well as other hydrocarbon substituents, may contain number designators indicating the number of carbon atoms in the substituent (i.e. Ci-C ₈ means one to eight carbons), although such designators may be omitted. Unless otherwise specified, the alkyl groups of the present invention contain 1 to 12 carbon atoms. For example, an alkyl group can contain 1-2, 1-3, 1- 4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6 or 5-6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. [0019] As used herein, the term "acyl" refers to an alkyl radical as described above, wherein the carbon atom attached to the remainder of a molecule is substituted with an oxo group so as to form a C=0 bond. Examples of acyl groups include, but are not limited to, acetyl, propionyl, and butyryl. [0020] As used herein, the term "cycloalkyl" refers to an alkyl group as described above, wherein the carbon chain is a cyclic carbon chain. The cycloalkyl groups of the present invention contain at least 3 carbon atoms.

[0021] As used herein, the term "one-pot reaction" refers to a reaction in which a starting material undergoes at least two sequential chemical transformations in a single reaction vessel. In general, compounds formed as intermediates in the sequence are not isolated from a one-pot reaction mixture. Reagents necessary to effect the transformation sequence may be added together at the beginning of the sequence, or they may be added one after another as the sequence progresses.

[0022] As used herein, the term "protecting reagent" refers to a reagent capable of reacting with a functional moiety to form a protecting group that renders the functional moiety unreactive. The protecting group is also removable so as to restore the functional moiety to its original state. A protecting reagent can be an "aldehyde protecting reagent" wherein the protected functional moiety is an aldehyde. Such reagents are capable of reacting with aldehydes to form protecting groups including acetals, monothioacetals, dithioacetals, and hydrazones. Various protecting groups and protecting reagents, including aldehyde protecting reagents, are well known to one of ordinary skill in the art and include compounds that are disclosed in Protective Groups in Organic Synthesis, 4th edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, 2006, which is incorporated herein by reference in its entirety. III. Embodiments of the Invention

[0023] The present invention provides a process for the preparation of substituted benzamides from substituted benzaldehydes. In one aspect, the invention provides a process for the preparation of a compound of formula Vic:

Vie The process includes: a) converting a compound of formula lie

lie

to a compound of formula Vc

in a one-pot reaction; and

b) oxidizing the compound of formula Vc under conditions suitable to provide the compound of formula Vic;

wherein:

R^ and R ² are independently selected from the group consisting of H; C _1-6 alkyl; C3-7 cycloalkyl; C3-7 cycloalkylmethyl; and C _1-4 alkyl which is partially or completely substituted with fluorine.

[0024] Throughout the specification, the use of a crossed imine double bond is meant to indicate cis, trans, or a mixture of cis and trans orientations about the double bond. [0025] In some embodiments, a substituted benzaldehyde lie is activated by converting it to a substituted benzaldehyde acetal. The substituted benzaldehyde acetal then reacts with 4- amino-3,5-dichloropyridine providing a substituted phenyl imine. The substituted phenyl imine is then oxidized to provide a substituted benzamide. In some embodiments, the one- pot reaction of step a), discussed above, comprises: i) converting a compound of formula (lie) under conditions sufficient to provide a compound of formula (IIIc)

ii) contacting the compound of formula IIIc with a compound of formula IVa

IVa

under conditions suitable to form the compound of formula Vc;

wherein:

R ⁴ and R ⁵ are independently selected from the group consisting of C _1-6 alkyl and acyl; or

R ⁴ and R ⁵ are taken together to form an optionally substituted 5-7 member cyclic ring.

[0026] Preferably, the one-pot reaction converting lie to Vc is conducted in a non-polar organic solvent under acidic conditions with or without an aldehyde protecting reagent. In some embodiments the invention provides a method for the preparation of a compound of formula Vic as described above, wherein: 1. the conversion of aldehyde lie to benzacetal

IIIc is conducted in a non-polar organic solvent in the presence of an acid; and 2. the one-pot conversion optionally includes an aldehyde protecting reagent. The organic solvent can be selected from suitable solvents including, but not limited to, toluene, xylene, and mixtures thereof. Acidic conditions can be maintained by using an acid such as ^-toluenesulfonyl acid (PTSA), camphorsulfonic acid, acetic acid, and the like. In some embodiments the inventive process includes a one-pot reaction as described above, wherein the non-polar organic solvent is selected from the group consisting of toluene and xylene. In some embodiments the inventive process includes a one-pot reaction as described above, wherein the acid is selected from the group consisting of ^-toluenesulfonic acid, camphorsulfonic acid, and acetic acid. [0027] Any suitable aldehyde protecting reagent may be used in the methods of the present invention. Suitable reagents are capable of reacting with aldehydes to form protecting groups, including but not limited to acetals, monothioacetals, dithioacetals, and hydrazones. Such protecting groups can be removed to restore the aldehyde moiety. In some embodiments the inventive process includes a one-pot reaction as described above, wherein the aldehyde protecting reagent is selected from the group consisting of trimethyl orthoformate (TMOF), triethyl orthoformate, triethyl orthoacetate, trimethyl orthoacetate, acetic anhydride, ethylene glycol, and propylene glycol. One of skill in the art will appreciate that still other aldehyde protecting reagents may be useful in the inventive process.

[0028] The oxidative conversion of Vc to Vic can be conducted under any suitable conditions. In particular, the present invention provides a process for preparing substituted benzamides via imine oxidation using aqueous conditions requiring neither strong bases nor dangerous acid derivatives. The process is safe, energy efficient, and environmentally friendly. In some embodiments, benzamide oxidation is conducted using a mixture of tetrahydrofuran and water. In some embodiments the inventive process includes the oxidation of Vc as described above, wherein the oxidation step includes an oxidant selected from the group consisting of a chlorite, a transition metal catalyst, nickel peroxide, meta- chloroperoxybenzoic acid (w-CPBA), tert-butyl hydroperoxide (TBHP), potassium peroxomonosulfate (Oxone), or mixtures thereof. In some embodiments, the chlorite is selected from the group consisting of chlorous acid, magnesium chlorite, sodium chlorite, and potassium chlorite. The oxidation step can be conducted in a buffered solution. In some embodiments, the oxidation step is conducted with a chlorite that is buffered with an electrolyte selected from the group consisting of HCl/sodium citrate, citric acid/sodium citrate, acetic acid/sodium citrate, potassium dihydrogen phosphate, dipotassium

phosphate/sodium dihydrogen phosphate, and disodium phosphate mixtures.

[0029] In some embodiments the present invention provides a process for preparing an N- substituted (3,4-dimethoxy)benzamide from a (3,4-dimethoxy)benzaldehyde, wherein the

(3,4-dimethoxy)benzaldehyde is activated by converting it to a (3,4-dimethoxy)benzacetal (as shown, for example, in Figure 1). The (3,4-dimethoxy)benzacetal then reacts with 4-amino- 3,5-dichloropyridine, resulting in an N-substituted (3,4-dimethoxy)benzylimine. The N- substituted (3,4-dimethoxy)benzylimine is then oxidized under conditions suitable to provide the N- substituted (3,4-dimethoxy)benzamide.

[0030] In some embodiments the present invention provides a process for preparing an N- substituted (3-cyclopropylmethoxy-4-difluoromethoxy)benzamide from a (3- cyclopropylmethoxy-4-difluoromethoxy)benzaldehyde, wherein the (3-cyclopropylmethoxy- 4-difluoromethoxy)benzaldehyde is activated by converting it to a (3-cyclopropylmethoxy-4- difluoromethoxy)benzacetal (as shown, for example, in Figure 2). The (3- cyclopropylmethoxy-4-difluoromethoxy)benzacetal then reacts with a substituted amine (for example, 4-amino-3,5-dichloropyridine), resulting in an N- substituted (3- cyclopropylmethoxy-4-difluoromethoxy)benzylimine. One of skill in the art will understand that a variety of substituted amines can be used in this process. The N-substituted (3- cyclopropylmethoxy-4-difluoromethoxy)benzylimine is then oxidized to afford the N- substituted (3-cyclopropylmethoxy-4-difluoromethoxy)benzamide. In some embodiments, the N- substituted (3-cyclopropylmethoxy-4-difluoromethoxy)benzamide is roflumilast. [0031] In some embodiments the present invention provides a process for preparing substituted benzamides as described above, wherein the compound of formula Vic is:

Vlb

[0032] In a related aspect, the present invention provides a process for the preparation of a compound of structure Vic

Vic

The process includes:

a) contacting a compound of formula lie

lie

with a compound of formula IVa

IVa

under conditions sufficient to provide a compound of formula Vc

Vc and b) oxidizing the compound of formula Vc under conditions suitable to provide the compound of formula Vic;

wherein

R ¹ are R ² independently selected from the group consisting of H; C _1-6 alkyl; C3-7

cycloalkyl; C3-7 cycloalkylmethyl; and C _1-4 alkyl which is partially or completely substituted with fluorine.

[0033] In general, the reaction conditions, oxidants, and buffering agents contemplated for use in this related aspect are as described above. In some embodiments, the conversion of Vc to Vic is conducted in a mixture of tetrahydrofuran and water. In some embodiments, the compound of formula Vic is:

VIb

[0034] In some embodiments, the present invention provides a process for preparing an N- substituted 3-cyclopropylmethoxy-4-difluoromethoxy benzamide by oxidation of the N- substituted imine obtained from a benzaldehyde and an aminopyridine. The molar ratio of the benzaldehyde to the aminopyridine is from 1 : 1 to 1 : 1.2. The amount of aminopyridine required is dramatically reduced as compared to known methods. For example, WO

2004/080967 requires a molar ratio of 1 : 1.8 to 1 :2.7 for a benzaldehyde derivative and an aminopyridine. Therefore, the inventive process as presently disclosed is more economically efficient. In some embodiments, the invention provides a process for the conversion of a compound of formula lib, below, to a compound of formula VIb, i.e. roflumilast. The compound of formula lib can be made according to WO 2008/15226.

Mb

[0035] In some embodiments, the conversion process includes: a) converting a compound of formula lib in a one-pot reaction under conditions sufficient to provide a compound of formula Illb

Illb ; and

b) reacting the compound of formula Illb with a compound of formula IVa

IVa

in the one-pot reaction under conditions suitable to form a compound of formula Vb

^Vb ; and

c) oxidizing the compound of formula Vb to provide the compound of formula VIb. [0036] In another aspect, the present invention provides a compound of formula Vc

Vc as well as a compound of formula IIIc

lllc

[0037] In some embodiments, the invention provides a compound of formula Vc:

Vc wherein:

R ¹ and R ² are independently selected from the group consisting of H; C _1-6 alkyl; C ₃ -7 cycloalkyl; C ₃ -7 cycloalkylmethyl; and C _1-4 alkyl which is partially or completely substituted with fluorine.

[0038] In some embodiments, the invention provides a compound of formula Vc wherein R ¹ and R ² are independently selected from the group consisting of C ₃ -7 cycloalkylmethyl and Ci-4 alkyl which is partially or completely substituted with fluorine.

[0039] In some embodiments, the compound of formula Vc has the formula:

Vb

[0040] In some embodiments, the invention provides a compound of formula IIIc:

lllc wherein:

R ¹ are R ² independently selected from the group consisting of H; C _1-6 alkyl; C3-7

cycloalkyl; C3-7 cycloalkylmethyl; and C _1-4 alkyl which is partially or completely substituted with fluorine; and

R ⁴ and R ⁵ are independently selected from the group consisting of C _1-6 alkyl and acyl; or

R ⁴ and R ⁵ are taken together to form an optionally substituted 5-7 member cyclic ring.

[0041] In some embodiments, the invention provides a compound of formula IIIc, wherein:

R ¹ and R ² are independently selected from the group consisting of C _1-6 alkyl; C3-7

cycloalkylmethyl; and C _1-4 alkyl which is partially or completely substituted with fluorine; and

R ⁴ and R ⁵ are independently selected from the group consisting of C _1-6 alkyl groups.

IV. Examples

[0042] The following examples are presented to describe the invention in further detail. However, the present invention is by no means restricted to the specific embodiments described herein.

Example 1

Synthesis of 3,5-dichloro-N-(3,4-dimethoxy)benzylidene)pyridin-4-amine(Va )

[0043] To a solution of 3,4-dimethoxybenzaldehyde (5 g, 30 mmol, 1.2 eq.) in toluene (25 mL) were added PTSA (103 mg, 0.6 mmol, 0.02 eq.) and TMOF (3.6 mL, 33 mmol, 1.32 eq.). The reaction mixture was heated to reflux for 2 hours and then cooled to 65 ± 5°C. 4-Amino- 3,5-dichloropyridine (4.1 g, 25 mmol, 1.0 eq.) and additional PTSA (413 mg, 2 mmol, 0.08 eq.) were added and the reaction mixture was then heated to 120°C and refluxed for 15 hours. The mixture was cooled to room temperature and w-heptane (40 mL) was added. The precipitate was filtered, and the crude product was recrystallized from DCM/w-heptane to give 2.8 g of the imine as a colorless solid. 1H NMR (300 MHz, CDC1 ₃ ) δ 8.47 (s, 2H), 8.23 (s, 1H), 7.64 (s, 1H), 7.38 (d, 1H, J= 8.4 Hz), 6.98 (d, 1H, J= 8.4 Hz), 3.99 (s, 3H), 3.98 (s, 3H).

Example 2

Synthesis of N-(3,5-dichloro-pyridin-4-yl)-3,4-dimethoxy-benzamide (Via) [0044] The imine Va of Example 1 (311 mg, 1.0 mmol, 1.0 eq) was dissolved in a mixture of THF (5 mL) and 2-methylbut-2-ene (1.1 mL, 10.0 mmol, 10.0 eq). NaC10 ₂ (452 mg, 5.0 mmol, 5.0 eq) was then added to the solution. The reaction mixture was vigorously stirred while an aqueous solution of NaH ₂ P0 ₄ (3.3 M, 1.5 mL, 5.0 mmol, 5.0 eq) was added dropwise. When the reaction was complete as assessed by TLC, the reaction mixture was diluted with DCM (30 mL) and washed with water, 10% aqueous Na ₂ S ₂ 0 ₃ , and brine (10 mL each). The organic layer was dried over MgS0 ₄ and solvents were evaporated to afford the crude benzamide (283 mg). 1H NMR (300 MHz, CDC1 ₃ ) δ 8.57 (s, 2H), 7.69 (s, 1H), 7.54- 7.52 (m, 3H), 6.97 (d, 1H, J= 9.0 Hz), 6.97 (s, 6H).

Example 3

Synthesis of 3,5-dichloro-N-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzylidene) pyridin-4-amine (Vb)

[0045] To a solution of lib (5.0 g, 20.6 mmol, 1.0 eq) in toluene (25 mL) were added PTSA (71 mg, 0.41 mmol, 0.02 eq) and TMOF (2.4 g, 22.6 mmol, 1.1 eq). The reaction mixture was heated to reflux for 2 hours. Then additional TMOF (2.4 g, 22.6 mmol, 1.1 eq) and PTSA (142 mg, 0.82 mmol, 0.04 eq) were added and heating was continued for 1 hour, after which the reaction was finished as assessed by TLC. The reaction temperature was lowered to 70-80°C, and IVa (2.5 g, 15.3 mmol, 0.75 eq) and PTSA (142 mg, 0.82 mmol, 0.04 eq) were added. The mixture again was heated to reflux. After 15 hours, additional PTSA (355 mg, 2.05 mmol, 0.1 eq) and IVa (1.8 g, 11 mmol, 0.54 eq) were added and heating was continued for another 15 hours. Then, the mixture was cooled to room

temperature and solvents were removed by evaporation. The residue was dissolved in dichloromethane and then washed with saturated aqueous NaHC0 ₃ and brine. The organic layer was dried over MgS0 ₄ and concentrated. The crude mixture was purified by column chromatography to afford 1.8 g (23% yield) of Vb as a colorless oil. 1H NMR (300 MHz, CDC1 ₃ ) δ 8.43 (s, 2H), 8.26 (s, 1H), 7.68 (s, 1H), 7.39-7.26 (m, 2H), 7.00-6.51 (t, 1H, J= 75 Hz), 4.00 (d, 2H, J= 6.9 Hz), 1.33 (m, 1H), 0.71-0.65 (m, 2H), 0.42-0.38 (m, 2H). ¹³ C NMR (125 MHz, CDC1 ₃ ) 6 165.38, 153.31, 150.98, 147.85, 144.15, 132.78, 124.23, 122.99, 122.29, 117.81 (CF ₂ , JcF = 260 Hz), 115.74 (CF ₂ ), 113.66 (CF ₂ ), 112.51, 74.01, 9.99, 3.22. ¹⁹ F NMR (282 MHz, CDC1 ₃ ) δ - 82.24, - 82.51. Example 3

Synthesis of 3-(cyclopropylmethoxy)-N-(3,5-dichloro-pyridin-4-yl)-4-(difl uoromethoxy) benzamide, (VIb; roflumilast).

[0046] 3-(cyclopropylmethoxy)-N-(3,5-dichloro-pyridin-4-yl)-4-(difl uoromethoxy) benzamide (VIb). Vb (387 mg, 1.0 mmol, 1.0 eq) was dissolved in a mixture of THF (5 mL) and 2-methylbut-2-ene (1.1 mL, 10.0 mmol, 10.0 eq), and then NaC10 ₂ (452 mg, 5.0 mmol, 5.0 eq) was added to the solution. The reaction mixture was vigorously stirred while an aqueous solution of NaH ₂ P0 ₄ (3.3 M, 1.5 mL, 5.0 mmol, 5.0 eq) was added dropwise. Upon reaction completion as assessed by TLC, the reaction mixture was diluted with EtOAc (30 mL) and washed with water, 10% aqueous Na ₂ S ₂ 0 ₃ , and brine (10 mL each). The organic layer was dried over MgS0 ₄ and solvents were evaporated to afford crude roflumilast VIb (400 mg).

[0047] Recrystallization of roflumilast. Crude roflumilast, IPA (6 mL), and purified water (2.1 mL) were added to a 25 mL flask. The mixture was stirred and heated to 75 ± 5°C to dissolve all material, and then the clear solution was cooled to the cloud point (55°C). The mixture was then held at the same temperature for 30 minutes. The mixture was cooled to 25 ± 5°C and continuously stirred at this temperature for 2 hours. The crystals were collected by filtration. The filter cake was washed with purified water and dried at 50 ± 5°C under reduced pressure to yield 230 mg (57% yield) of roflumilast as a colorless solid. 1H NMR (300 MHz, CDC1 ₃ ) δ 8.58 (s, 2H), 7.66 (s, 1H), 7.59 (d, 1H, J= 2.1 Hz), 7.49 (dd, 1H, J= 2.1, 8.4 Hz), 7.31 (d, lH, J= 8.4 Hz), 7.00-6.50 (t, 1H, J= 74.7 Hz), 3.98 (d, 2H, J= 6.9), 1.4-1.2 (m, 1H), 0.70-0.67 (m, 2H), 0.39-0.37 (m, 2H). ¹³ C NMR (125 MHz, CDC1 ₃ ) δ 163.70, 150.99, 148.38, 143.94, 139.70, 130.88, 128.91, 122.36, 119.93, 117.76 (CF ₂ , J _CF = 261 Hz), 115.68 (CF ₂ ), 114.32, 113.66 (CF ₂ ), 74.26, 10.02, 3.29. ¹⁹ F NMR (282 MHz, CDC1 ₃ ) δ - 82.35, - 82.62.

[0048] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.