US 201502.46884A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0246884 A1 Salaet Ferré et al. (43) Pub. Date: Sep. 3, 2015

(54) PROCESS FOR PREPARING ROFLUMLAST Publication Classification (71) Applicant: INTERQUIM, S.A., Sant Cugat del (51) Int. Cl. Valles - Barcelona (ES) C07D 213/75 (2006.01) C07D 249/10 (2006.01) (72) Inventors: Josep Salaet Ferré, Sant Cugat del C07D 233/90 (2006.01) Valles - Barcelona (ES); Francisco (52) U.S. Cl. Marquillas Olondriz, Sant Cugat del CPC ...... C07D 213/75 (2013.01); C07D 233/90 Valles - Barcelona (ES) (2013.01); C07D 249/10 (2013.01) (73) Assignee: INTERQUIM, S.A., Sant Cugat del Valles - Barcelona (ES) (57) ABSTRACT (21) Appl. No.: 14/426,881 (22) PCT Fled: Oct. 16, 2013 The invention relates to a process for the preparation of Rof lumilast by reaction of an activated form of 3-(cyclopropyl (86) PCT NO.: PCT/EP2013/071607 methoxy)-4-(difluoromethoxy)-benzoic acid with an activat S371 (c)(1), ing agent selected from (a) carbonyldiimidazole (CDI), (b) (2) Date: Mar. 9, 2015 1,1-carbonyl-di-(1,2,4-triazol) (CDT), (c) 1.1'-carbonyl-bis (2-methylimidazol), (d), 1-carbonyl-dipyperidin, (e) N.N'- Related U.S. Application Data dicyclohexylcarbodiimide (DCC), (f) N,N'-diisopropylcar (60) Provisional application No. 61/738,028, filed on Dec. bodiimide (DIC), (g) 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and a combination of one of the previous 17, 2012. (a)-(g) with (h) N-hydroxysuccinimide or (i) N-hydroxyph (30) Foreign Application Priority Data thalimide, and the subsequent reaction with 3,5-dichloropy ridine-4- in the presence of an inorganic base. The Oct. 17, 2012 (ES) ...... P201 231598 invention also relates to the synthesis intermediates. Patent Application Publication Sep. 3, 2015 US 2015/0246884 A1

sis

te o : s N 9) l

g 8 8 g 8 3. 3. 8 3. 3. g 8 8 8 8: US 2015/0246884 A1 Sep. 3, 2015

PROCESS FOR PREPARING ROFLUMLAST -continued

FIELD OF THE INVENTION Auo COOH SOCl. He 0001. The present invention is comprised within the pro cedures for obtaining Roflumilast, a phosphodiesterase IV FHCO inhibitor compound. (II) NH2 PRIOR STATE OF THE ART C C 0002 Roflumilast compound is a phosphodiesterase IV inhibitor compound, of clinical application as antiallergic and antiasthmatic. It corresponds chemically to 3-(cyclopropyl Au N1 NaH methoxy)-N-(3,5-dichloropyridine-4-yl)-4-(difluo O C (III)III romethoxy)-benzamide and its structural formula is: FHCO

(I) O C 21 h Auo 1S H C FHCO FHCO Roflumilast (I) Roflumilast 0005. The process claimed in WO2004080967 is based on the reaction of an activated derivative of 3-(cyclopropyl 0003. The preparation of roflumilast (I) has been methoxy)-4-difluoromethoxy-3-methoxybenzoic acid (pref described in the following patent documents: WO950 1338, erably acyl chloride) and an alkaline salt of 3,5-dichloropy WO2004033430, WO2004080967, WO2005026095 and ridine-4-amine (preferably potassium salt) characterised in IN478/MUMA2004. that the molar ratio of alkaline salt of 3,5-dichloropyridine 0004. In WO950 1338 the reaction of 3-(cyclopropyl 4-amine and the activated derivative is 1.5-3, preferably 1.8- methoxy)-4-hydroxy-benzaldehyde with chlorodifluo 2.7. The reaction is performed preferably in tert-BuOK and romethane in the presence of sodium hydroxide and benzyl or N-methylpyrrolidone. trimethylammonium chloride (BTMA) in dioxane/ 0006 WO2005026095 describes a process where alkyla leads to 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-ben tion of 3,4-dihydroxy-benzoate methyl with bromomethyl Zaldehyde, which by oxidation with sodium chlorite and sul cyclopropane in the presence of in phamic acid yields 3-(cyclopropylmethoxy)-4-(difluo acetone leads to methyl 3-(cyclopropylmethoxy)-4-hydroxy romethoxy)-benzoic acid. Chlorination of this acid with benzoate, which by reaction with chlorodifluoromethane in thionyl chloride in reflux provides the corresponding the presence of sodium hydroxide and tetrabutylammonium acyl chloride, which is finally condensed with 3,5-dichloro bromide in toluenefwater yields 3-(cyclopropylmethoxy)-4- pyridine-4-amine in the presence of sodium hydride in tet (difluoromethoxy)-methyl benzoate. Hydrolysis of the rahydrofuran to thus reach roflumilast (I). These procedures methyl ester group with sodium hydroxide in water provides are set out in Scheme 1. the corresponding 3-(cyclopropylmethoxy)-4-(difluo romethoxy)-benzoic acid. The latter, by treatment with thio nyl chloride in the presence of catalytic dimethylformamide Scheme 1 at 90°C., provides the corresponding acid chloride. The reac tion of acid chloride with 3,5-dichloropyridine-4-amine in O ls the presence of sodium hydride in tetrahydrofuran leads to Au O H F F roflumilast (I). These procedures are set out in Scheme 2. NaOH, BTMA

HO Scheme 2 O HO COOMe Br Auo HsNaClO2, H2O HNSOH Hs AcOH K2CO3 FHCO HO US 2015/0246884 A1 Sep. 3, 2015

-continued -continued C OCHF Auo COOMe F 1. F O CO, Pd cat. NaOH, BuNBr ROH He HO base

Auo COOMe NaOH Br -e-

FHCO COOR Auo base Auo COOH SOCI2, DMF -e-

FHCO (II) COOH NH2 Auo SOCl. C C N FHCO O 2 (II) O Au C (III)N NaH FHCO C C O C 21 h O O Au 1s Au C —- H NaH C FHCO FHCO Roflumilast (I) O C 21 h 0007 WO2004033430 describes the preparation of Rof lumilast (I) according to Scheme 3. Auo 1S H C Scheme 3 FHCO OH Roflumilast (I) OH Aut -e- base 0008 IN478/MUM/2004 describes the preparation of OH Roflumilast (I) by treatment of 3,4-dihydroxybenzaldehyde with excess alkaline salt of formulaYCFCOOA, where Y is halogen and A is an alkaline metal, in wet , followed -e- CH2Cl2, -60° C. by reaction of 4-(difluoromethoxy)-3-hydroxy-benzaldehyde thus formed with bromomethyl cyclopropane in the presence of potassium carbonate in dimethylformamide. The 3-(cyclo OH C propylmethoxy)-4-(difluoromethoxy)-benzaldehyde obtained is then subject to oxidation with sodium chlorite in ls an acid medium. The resulting 3-(cyclopropylmethoxy)-4- F F (difluoromethoxy)-benzoic acid is made to react with thionyl chloride to form the corresponding acid chloride, which sub sequently is made to react with 3,5-dichloropyridine-4-amine Br in the presence of sodium hydride in tetrahydrofuran to reach Roflumilast (I). These procedures are set out in Scheme 4. US 2015/0246884 A1 Sep. 3, 2015

3,5-dichloropyridine-4-amine, which represents an eco Scheme 4 nomic and environmental drawback. 0011. Therefore, according to the procedures described to O YCFCOOA SO date, it is concluded that a new procedure should be available HO for obtaining industrially Roflumilast (I) that uses more H - So acceptable bases on an industrial basis, avoids the formation of intermediates and the use of reagents that may be toxic, and HO limits the excesses of 3,5-dichloropyridine-4-amine. O BRIEF DESCRIPTION OF THE INVENTION HO H 0012. This invention provides a new, advantageous proce dure for obtaining Roflumilast (I), that can be implemented FHCO industrially, that uses activated forms of acid other than acid O chloride, which is considered due to its structure as being a compound with genotoxic activity, thus avoiding also the use

Au Br Auo HeNaClO3, H' of thionyl chloride, a toxic, corrosive agent, in the preparation of these activated forms. As an additional advantage, the K2CO3 procedure of the present invention allows obtaining Roflumi FHCO last with yields higher than 80%. 0013 Therefore, in a first embodiment this invention is Auo COOH SOCl. aimed at a process for the preparation of a compound of -- formula (IV): FHCO (II) (IV) NH2 C C N A-s-s-s

O 2 FHCO O Au C (III)N NaH 0014 where L is (a) 1H-imidazol-1-yl, (b) 1H-1,2,4-tria Zol-1-yl, (c) 2-methyl-1H-imidazol-1-yl, (d) piperidin-1-yl, FHCO (e) N,N'-dicyclohexylcarbamimidoyloxy, (f) N,N'-diisopro C pylcarbamimidoyloxy, (g) N'-(3-(dimethylamino)propyl)-N- O 21 h ethylcarbamimidoyloxy, (h) 2,5-dioxopyrrolidin-1-yloxy, or Au O 1S (i) 1,3-dioxoisoindolin-2-yloxy, H 0015 comprising: C 0016 i) activation of a compound of formula (II): FHCO Roflumilast (I) (II)

COOH 0009 Finally, variation of the above procedures have been Auo submitted in CN102276522 CAPLUS 2011:1626719, CN102336703 CAPLUS 2012: 170113, CN102336704 FHCO CAPLUS 2012:1701.99, CN102336705 CAPLUS 2012:170217 and CN102351787 CAPLUS 2012:242.538. 0017 with an activating agent selected, respectively, 0010. In summary, the routes known to date involve the from (a) carbonyldiimidazole (CD), (b) 1, 1'-carbo use of very strong bases, as in the case of sodium hydride or nyl-di-(1,2,4-triazol) (CDT), (c) 1.1'-carbonyl-bis-(2- tert-BuOK, that are not advisable in industrial processes due methylimidazole), (d) 1.1'-carbonyl-dipiperidine, (e) to the danger involved in handling them. Another disadvan N,N'-dicyclohexylcarbodiimide (DCC), (f) N,N'-di tage of the procedures of the previous state of the art is the isopropylcarbodiimide (DIC), (g) 1-ethyl-3-(3-dim formation of the intermediate 3-(cyclopropylmethoxy)-4-(di ethylaminopropyl)carbodiimide (EDC) and a combi fluoromethoxy)benzoyl chloride (II); for its structure, this nation of one of the previous with (h) intermediate is considered to involve a potential risk of geno N-hydroxysuccinimide or (i) N-hydroxyphthalimide toxicity, which would lead to limiting its contents in the final in an adequate , product according to the regulations for this type of com 0018 and, optionally pounds. In addition, thionyl chloride, a toxic reagent, is used 0.019 ii) isolation of the compound of formula (IV). in the formation of this intermediate. Finally, 0020. The compounds of formula (IV) allow obtaining WO2004080967 highlights the need to use large excesses of Roflumilast by a process including, as main advantage, the US 2015/0246884 A1 Sep. 3, 2015

use of bases alternative to sodium hydride or tert-BuOK, that BRIEF DESCRIPTION OF THE FIGURES are much more advisable in a industrial process, where it is not necessary to use a high excess of 3,5-dichloropyridine-4- 0026 FIG. 1. shows the X-ray powder diffraction diagram amine. In fact, this process can work adequately with 1-1.5 for the Roflumilast obtained by the process of this invention. equivalents of 3,5-dichloropyridine-4-amine for each acid The intensity, in the y-axis, is expressed in a counting linear equivalent, which involves cost savings in the process and an scale. The abscissa corresponds to the angle 20°. environmental improvement. All these characteristics pro vide safety, environmental and economic advantages over the procedures known in the state of the art. DETAILED DESCRIPTION OF THE INVENTION 0021. Therefore, an additional embodiment of this inven 0027. The process for obtaining the compound of formula tion is aimed at the use of compounds of formula (IV) for (IV) responds to the following scheme (I): obtaining Roflumilast. 0022. Another additional embodiment of the invention is aimed at a process for obtaining Roflumilast that comprises Scheme I the preparation of a compound of formula (IV), as previously described, and the Subsequent reaction of the compound of AA formula (IV) with 3,5-dichloropyridine-4-amine, compound Hep of formula (III): FHCO (III) (II) NH2 O C C Auo L

FHCO (IV) 0023 in the presence of an inorganic base selected among alkaline hydroxides, alkaline carbonates and alkaline fluo rides, in an adequate solvent, and, optionally, in the presence 0028 where: of a drying agent. 0029 AA means an activating agent selected from (a) 0024. An additional embodiment of this invention relates carbonyldiimidazole (CD), (b) 1, 1'-carbonyl-di-(1,2,4-tria to an intermediate compound of formula (IV): Zol) (CDT), (c) 1.1'-carbonyl-bis-(2-methylimidazole), (d) 1,1-carbonyl-dipiperidin, (e) N,N'-dicyclohexylcarbodiim ide (DCC), (f) N,N'-diisopropylcarbodiimide (DIC), (g) (IV) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and a combination of one of the previous (a)-(g) with (h) N-hy droxysuccinimide or (i) N-hydroxyphthalimide: A-s-s-s 003.0 L means respectively (a) 1H-imidazol-1-yl, (b) 1H-1,2,4-triazol-1-yl, (c) 2-methyl-1H-imidazol-1-yl, (d) FHCO piperidin-1-yl, (e) N.N'-dicyclohexylcarbamimidoyloxy, (f) N,N'-diisopropylcarbamimidoyloxy, (g) N'-(3-(dimethy lamino)propyl)-N-ethylcarbamimidoyloxy, (h) 2.5-dioxopy 0025 where L is selected from (a) 1H-imidazol-1-yl, (b) 1H-1,2,4-triazol-1-yl, (c) 2-methyl-1H-imidazole-1-yl, (d) rrolidin-1-yloxy and (i) 1,3-dioxoisoindolin-2-yloxy. piperidin-1-yl, (h) 2.5-dioxopyrrolidin-1-yloxy and (i) 1,3- 0031 Table 1 shows the meaning of the activating agents dioxoisoindolin-2-yloxy, AA and of the corresponding L. groups.

TABLE 1.

AA activating agent

a) carbonyldiimidazole O (CDI) 1. US 2015/0246884 A1 Sep. 3, 2015

TABLE 1-continued AA activating agent b) 1,1'-carbonyl-di- O 1H-1,2,4-triazol- N (1,2,4-triazol) (CDT) 1-yl -N M S.

c) 1.1'-carbonyl-bis-(2- O 2-methyl-1H methylimidazole) HC imidazol-1-yl

N e S. H3C H3C N

d) 1,1'-carbonyl- O piperidine-1-yl dipiperidine ls -N ) N N

e) N,N'-dicyclohexyl cHX N,N'-dicyclohexyl cHX carbodiimide (DCC) N1 carbamimidoyloxy HN1 C Se-N cHX No1'sC S. 1 cHX f) N,N'-diisopropyl Pr N,N'-diisopropyl Pr carbodiimide (DIC) N1 carbamimidoyloxy HN1 C S1N iPr No-1'sC Sa 1 iPr g) 1-ethyl-3-(3- -C2H5 N'-(3- CH5 dimethylaminopropyl) N (dimethylamine) HN1 carbodiimide (EDC) propyl)-N-ethyl C CH carbamimidoylox C CH S1a1nN 13 No.1'sS1\1\ 3 CH3 CH

h) N-hidroxysuccinimide O 2.5- O dioxopyrrollidin-1- yloxy \ HO-N O-N

O O

i) N- O 1,3- O hydroxyphthalamide dioxoisoindolin 2-yloxy \ HO-N O-N

O O

0032. In a preferred embodiment, the activating agent is diimidazole (CDI), (b) 1,1-carbonyl-di-(1,2,4-triazol) selected from (a) carbonyldiimidazole (CDI), (b) 1,1'-carbo (CDT) and (c) 1.1'-carbonyl-bis-(2-methylimidazole). In a nyl-di-(1,2,4-triazol) (CDT), (c) 1.1'-carbonyl-bis-(2-meth more preferred embodiment, the activating agent is (a) car ylimidazole), (d) 1.1'-carbonyl-dipiperidin, and a combina bonyldiimidazole (CDI) or (b) 1, 1'-carbonyl-di-(1,2,4-tria tion of one of the previous (a)-(d) with (h) Zol) (CDT), and the resulting activated intermediate is the N-hydroxysuccinimide or (i) N-hydroxyphthalimide: More compound of formula (IV) where L is (a) 1H-imidazol-1-yl preferably, the activating agent is selected from (a) carbonyl (IVa) or (b) 1H-1,2,4-triazol-1-yl (IVb) respectively. US 2015/0246884 A1 Sep. 3, 2015

0033. In another preferred embodiment, the solvent of step 0044) iii) reaction of the compound of formula (IV) (i) is selected from dimethylsulphoxide, dimethylformamide, with 3,5-dichloropyridine-4-amine, in the presence of dymethylacetamide, tetrahydrofuran, methyl-tetrahydrofu an inorganic basic selected among alkaline hydroxides, ran, acetone, methyl ethyl ketone, methyl isobutyl ketone, alkaline carbonates and alkaline fluorides, in an dichloromethane, and mixtures thereof. adequate solvent, and, optionally, in the presence of a 0034. In a more preferred embodiment, the solvent of step drying agent. (i) is selected from tetrahydrofuran, dimethylsulphoxide, and 0045. This process has the following scheme (II): mixtures thereof. 0035. In an even more preferred embodiment, the solvent of step (i) is dimethylsulphoxide. Scheme II 0036) Optionally, the compound of formula (IV) can be isolated by conventional methods known by a person skilled in the art. Auo COOH AA 0037. The starting compounds of formula (II) can be pre He pared from methods known by a person skilled in the art, Such as those described in the documents of the state of the art FHCO mentioned in the background of this invention. Examples 1 and 2 set out in this document describe also a procedure for (II) obtaining it. NH2 0038. The compounds of formula (IV) can be used as C C reagents for the preparation of Roflumilast as described N above. 0039. Therefore, an additional aspect of this invention O 2 relates to a process for obtaining Roflumilast that comprises: O Au L (III)N 0040 i) activation of a compound of formula (II): Base

FHCO (II) (IV) C Auo COOH O 21 h AuO 1S FHCO H C 0041 with an activating agent selected from (a) car FHCO bonyldiimidazole (CD), (b) 1.1'-carbonyl-di-(1,2,4- Roflumilast (I) triazol) (CDT), (c) 1.1'-carbonyl-bis-(2-methylimida zole), (d) 1.1'-carbonyl-dipiperidin, (e) N,N'- dicyclohexylcarbodiimide (DCC), (f) N,N'- 0046 where AA and L are defined as above. diisopropylcarbodiimide (DIC), (g) 1-ethyl-3-(3- 0047. In a preferred embodiment, the activating agent is dimethylaminopropyl)carbodiimide (EDC) and a selected from (a) carbonyldiimidazole (CDI), (b) 1, 1'-carbo combination of one of the previous with (h) N-hy nyl-di-(1,2,4-triazol) (CDT), (c) 1.1'-carbonyl-bis-(2-meth droxysuccinimide or (i) N-hydroxyphthalimide in an ylimidazole), (d) 1.1'-carbonyl-dipiperidin, and a combina adequate solvent, to give an activated compound of tion of one of the previous with (a)-(d) with (h) (II), of general formula (IV): N-hydroxysuccinimide or (i) N-hydroxyphthalimide. More preferably, the activating agent is selected from (a) carbonyl diimidazole (CDI), (b) 1,1'-carbonyl-di-(1,2,4-triazol) (IV) (CDT) and (c) 1.1'-carbonyl-bis-(2-methylimidazole). In a more preferred embodiment, the activating agent is (a) car bonyldiimidazole (CDI) or (b) 1, 1'-carbonyl-di-(1,2,4-tria A-s-s-s Zol) (CDT), and the resulting activated intermediate is the compound of formula (IV) where L is (a) 1H-imidazol-1-yl FHCO (IVa) or (b) 1H-1,2,4-triazol-1-yl (IVb) respectively. 0048. In another preferred embodiment, the solvent of step 0042 where L is, respectively, (a) 1H-imidazol-1-yl, (i) is selected from dimethylsulphoxide, dimethylformamide, (b) 1H-1,2,4-triazol-1-yl, (c) 2-methyl-1H-imida dimethylacetamide, tetrahydrofuran, methyl-tetrahydrofu Zole-1-yl, (d) piperidin-1-yl, (e) N,N'-dicyclohexyl ran, acetone, methyl ethyl ketone, methyl isobutyl ketone, carbamimidoyloxi, (f) N,N'-diisopropylcarbamim dichloromethane, and mixtures thereof. idoyloxi, (g) N'-(3-(dimethylamino)propyl)-N- 0049. In a more preferred embodiment, the solvent of step ethylcarbamimidoyloxy, (h) 2.5-dioxopyrrolidin-1- (i) is selected from tetrahydrofuran, dimethylsulphoxide and yloxy or (i) 1,3-dioxoisoindolin-2-yloxy; mixtures thereof. 0043 ii) optionally, isolation of the compound of for 0050. In an even more preferred embodiment, the solvent mula (IV); and of step (i) is dimethylsulphoxide. US 2015/0246884 A1 Sep. 3, 2015

0051 Optionally, the compound of formula (IV) can be 0064 or L is (b) 1H-1,2,4-triazol-1-yl, of formula (IVb) isolated by conventional methods known by a person skilled in the art. 0052. In a preferred embodiment, the percentage of the (IVb) compound of formula (III) is 1-1.5 equivalents with respect to O the compound of formula (II). N 0053. In another preferred embodiment, in step (iii) alka Auo N e line hydroxides are selected from lithium hydroxide, sodium y hydroxide, potassium hydroxide, and hydroxide. N 0054. In another preferred embodiment, alkaline carbon FHCO N ates are selected from potassium carbonate and caesium car bonate. 0065. This invention is illustrated additionally by the fol 0055. In another preferred embodiment, alkaline fluoride lowing examples, that do not intend to limit its scope. is . 0056. In another preferred embodiment, the inorganic EXAMPLES base of step (iii) is sodium hydroxide or caesium carbonate, in the presence of a drying agent, or caesium fluoride. More Example 1 preferably, the inorganic base is caesium fluoride. Preparation of 3-(cyclopropylmethoxy)-4-(difluo 0057. In another preferred embodiment, the molar ratio of romethoxy)-benzaldehyde the inorganic base of step (iii) to 3-(cyclopropylmethoxy)-4- (difluoromethoxy)-benzoic acid (II) is 1.2-3 and preferably 0.066 55 g of 4-(difluoromethoxy)-3-hydroxybenzalde 2.4-2.8 base equivalents with respect to (II). hyde, 42.42 g of KCO (1.05 eq), 4.86 g of KI (0.1 eq) and 0058. In another preferred embodiment, the solvent of step 220 mL of dimethylsulphoxide (DMSO) were loaded in a (i) is selected from dimethylsulphoxide, dimethylformamide, reactor. The mixture was heated at 70° C. and kept for 1 h. A dimethylacetamide, tetrahydrofuran, methyl-tetrahydrofu mixture previously prepared of 42.65 g of bromomethyl ran, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclopropane (1.08 eq) and 110 mL of DMSO was added for dichloromethane, and mixtures thereof. More preferably the 1 hour. The reaction was kept for 3 hat 70°C., and then cooled solvent of step (iii) is dimethylsulphoxide. at room temperature. Once the temperature was reached, 375 0059. In another preferred embodiment, when the pres mL of toluene was added. The suspension was filtered to ence of a drying agent is necessary, it is selected from mag remove the remaining KCO, and then it was cooled at 0-5° nesium Sulphate and sodium Sulphate. C., and 375 mL of deionised water were loaded. The phases 0060. In another preferred embodiment, the inorganic were separated and the organic phase was washed twice with base is caesium fluoride and the solvent is dimethylsulphox 55 mL of deionised water. The solvent was removed at ide (DMSO), thus avoiding the use of dimethylformamide, a reduced pressure, obtaining 70 g (yield 99%) of 3-(cyclopro more toxic solvent than DMSO. pylmethoxy)-4-(difluoromethoxy)-benzaldehyde as a vis 0061 Another object of this invention is a compound of cous yellowish fluid. general formula (IV): Example 2 Preparation of (IV) 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (II) 0067 40 g of 3-(cyclopropylmethoxy)-4-(difluo A-s-s-s romethoxy)-benzaldehyde 160 mL of glacial acetic acid and 32.0 g of sulphamic acid (2.0 eq) were loaded in a reactor. The FHCO mixture was cooled at 5-10°C. and the temperature was not allowed to exceed 20° C., adding slowly a previously pre 0062 where L is (a) 1H-imidazol-1-yl, (b) 1H-1,2,4-tria pared solution of 44.77 g of sodium chloride and 61 mL of Zol-1-yl, (c) 2-methyl-1H-imidazol-1-yl, (d) piperidin-1-yl, deionised water. After the addition, the reaction was kept for (h) 2,5-dioxopyrrolidin-1-yloxy or (i) 1,3-dioxoisoindolin-2- 1 hour at 15-20°C. 450 mL of deionised water was loaded and yloxy. then it was cooled at 0-5°C. and kept for 1 h at this tempera 0063 More preferably, the compounds of general formula ture. The solid was filtered and washed four times with 200 (IV) are also object of this invention, where L is (a) 1H-imi mL of deionised water. The product was dried for 15 hat 40° dazol-1-yl, of formula (IVa) C., obtaining 36 g (yield 85%) of 3-(cyclopropylmethoxy)- 4-(difluoromethoxy)-benzoic acid (II) as solid. Example 3 (IVa) Preparation of Roflumilast (I) Auo Preparation of (3-(cyclopropylmethoxy)-4-(difluo romethoxy)-phenyl)(1H-imidazol-1-yl)-methanone FHCO (IVa) 0068 50 mL of tetrahydrofuran (THF) were added to 5.0 g of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic US 2015/0246884 A1 Sep. 3, 2015

acid (II) and 3.46 g of CDI (1.1 eq). The mixture was stirred react at this temperature for 6 h. Once the reaction was com for 2 hat room temperature. Then, the THF was removed by pleted, 100 mL of water were added and the pH was adjusted distillation, obtaining (3-(cyclopropylmethoxy)-4-(difluo to pH=5.0 with 1 NHC1. Product precipitation was seen and romethoxy)-phenyl)(1H-imidazol-1-yl)-methanone (IVa) as isolated by filtration. The filtered solid was washed with 100 Viscous oil. mL of H2O. The washed solid was dried in a vacuum oven for 0069. H-RMN (DMSO-D): 8.07 (s, 1H), 7.86 (s, 1H), 14 h at 50° C. 15.3 g of raw product were obtained and 7.64-7.57 (m, 2H), 7.27-7.12 (m, 2H), 7.12 (s, 1H), 3.95-3.92 recrystallised with a mixture of isopropanol-water at 90%. (d. 2H, J=12 Hz), 1.30-1. 19, (m. 1H), 0.60-0.34 (dm, 4H). The recrystallised solid was dried in a vacuum oven at 50° C. 0070 °C-RMN (DMSO-D): 167.44 (C), 149.53 (C), 13.90 g of roflumilast were obtained (yield 88%). 143.12 (C), 135.27 (CH), 130.59 (C), 122.38 (CH), 121.57 0077. The X-ray diffraction diagram is consistent with (CH), 120.31 (CH), 116.68 (CH), 114.99 (CH), 112.58 (CH), that of Example 3. 73.28 (CH), 10.11 (CH), 3.18 (CH). Example 5 Formation of Roflumilast (0071 60 mL of DMSO were added to 3.79 g of 3.5- Preparation of Roflumilast (I) dichloropyridin-4-amine (III) (1.2 eq) and 0.891 g of NaOH (1.15 eq). The mixture was stirred at a temperature of 50° C. Preparation of (3-(cyclopropylmethoxy)-4-(difluo for 2 h. A suspension was obtained to which 7.426 g of romethoxy)-phenyl)(1H-imidazol-1-yl)-methanone anhydrous NaSO were added as drying agent. (IVa) 0072 (3-(cyclopropylmethoxy)-4-(difluoromethoxy)- phenyl)(1H-imidazol-1-yl)-methanone (IVa) is dissolved in (0078 30 mL of THF were added to 5.0 g of 3-(cyclopro 40 mL of DMSO and this solution is slowly added over the pylmethoxy)-4-(difluoromethoxy)-benzoic acid (II) and 3.77 previous mixture for 30 minata temperature of 25-30°C. The g of CDI (1.2 eq). The mixture was stirred for 2 hat room reaction was allowed to react at this temperature for 16 h. temperature. Then, THF was removed by distillation and Once the reaction was completed, 150 mL of water were replaced by 30 mL of DMSO. A solution of (3-(cyclopropy added and the pH was adjusted to pH-7.0 with 1 N HC1. lmethoxy)-4-(difluoromethoxy)-phenyl)(1H-imidazol-1- Product precipitation was seen and isolated by filtration. The yl)-methanone (IVa) in DMSO was thus obtained. filtered solid was washed consecutively with 100 mL of 5% NaHCO, 100 mL of 0.01 NHCl 0.01N and 100 mL of H.O. Formation of Roflumilast The washed solid was dried in a vacuum oven for 14 hat 50° (0079 50 mL of DMSO were added to 4.42 g of 3.5- C.5.44 g of raw product were obtained and recrystallised with dichloropyridin-4-amine (III) (1.4 eq) and 15.14 g of CsCO a mixture of isopropanol-water at 90%. The recrystallised (2.4 eq). The mixture was stirred at a temperature of 90°C. for solid was dried in a vacuum oven at 50° C. 4.90 g of Roflu 3 h. A Suspension was obtained. milast were obtained (yield 63%). 0080 A solution in DMSO of (3-(cyclopropylmethoxy)- 0073 X-ray (angle values 2-theta (0): 5.5; 12.3; 16.1: 4-(difluoromethoxy)-phenyl)(1H-imidazol-1-yl)-methanone 16.6; 18.1; 22.4; 22.6; 24.1; 24.4; 24.7 and 26.9 measured in (IVa) was slowly added to 30 min. over the previous suspen an X-ray diffractometer with radiation Cu Ko (1,5406 A) sion at a temperature of 90-95°C. The reaction was allowed (FIG. 1). to react at this temperature for 6 h. Once the reaction was Example 4 completed, 75 mL of water were added and the pH was adjusted to pH-2.0 with 1 NHC1. Product precipitation was Preparation of Roflumilast (I) seen and isolated by filtration. The filtered solid was washed with 100 mL of H.O.The washed solid was dried in a vacuum Preparation of (3-(cyclopropylmethoxy)-4-(difluo oven for 14h at 50° C. 5.94 g of raw product were obtained romethoxy)-phenyl)(1H-imidazol-1-yl)-methanone and recrystallised with a mixture of isopropanol-water at (IVa) 90%. The recrystallised solid was dried in a vacuum oven at 50° C. 5.35 g of Roflumilast were obtained (yield 68%). 0074 30 mL of DMSO were added to 10.0 g of 3-(cyclo I0081. The X-ray diffraction diagram is consistent with propylmethoxy)-4-(difluoromethoxy)-benzoic acid (II) and that of Example 3. 7.54 g of CDI (1.2 eq). The mixture was stirred for 3 hat room temperature. Then, THF was removed by distillation and replaced by 40 mL of DMSO. A solution of (3-(cyclopropy Example 6 lmethoxy)-4-(difluoromethoxy)-phenyl)(1H-imidazol-1- yl)-methanone (IVa) in DMSO was thus obtained. Preparation of Roflumilast (I) Formation of Roflumilast Preparation of (3-(cyclopropylmethoxy)-4-(difluo romethoxy)-phenyl)(1H-1,2,4-triazol-1-yl)-metha 0075 50 mL of DMSO were added to 7.58 g of 3,5- dichloropyridin-4-amine (III) (1.2 eq) and 16.47 g of CsP (2.8 none (IVb) eq). The mixture was stirred at a temperature of 90° C. for 3 I0082 15 mL of DMSO were added to 5.0 g of 3-(cyclo h. A Suspension was obtained. propylmethoxy)-4-(difluoromethoxy)-benzoic acid (II) and 0076 A solution in DMSO of (3-(cyclopropylmethoxy)- 3.81 g of CDT (1.2 eq). The mixture was stirred for 2 hat 4-(difluoromethoxy)-phenyl)(1H-imidazol-1-yl)-methanone room temperature. A solution of (3-(cyclopropylmethoxy)-4- (IVa) was slowly loaded over the previous suspension for 30 (difluoromethoxy)-phenyl)(1H-1,2,4-triazol-1-yl)-metha minata temperature of 90-95°C. The reaction was allowed to none (IVb) in DMSO was thus obtained. US 2015/0246884 A1 Sep. 3, 2015

Formation of Roflumilast where L is (a) 1H-imidazol-1-yl, (b) 1H-1,2,4-triazol-1-yl, I0083 25 mL of DMSO were added to 3.79 g of 3.5- (c) 2-methyl-1H-imidazol-1-yl, (d) piperidin-1-yl, (e) dichloropyridin-4-amine (III) (1.2 eq) and 8.23g of CsP (2.8 N,N'-dicyclohexylcarbamimidoyloxy, (f) N,N'-diiso eq). The mixture was stirred at a temperature of 90° C. for 3 propylcarbamimidoyloxy, (g) N'-(3-(dimethylamino) h. A Suspension was obtained. propyl)-N-ethylcarbamimidoyloxy, (h) 2,5-dioxopyrro 0084. A solution of (3-(cyclopropylmethoxy)-4-(difluo lidin-1-yloxy, or (i) 1,3-dioxoisoindolin-2-yloxy, romethoxy)-phenyl)(1H-1,2,4-triazol-1-yl)-methanone comprising: (IVb) in DMSO was slowly loaded over the previous suspen sion in DMSO at a temperature of 90-95°C. The reaction was i) activation of a compound of formula (II): allowed to react at this temperature for 3 h. Once the reaction was completed, 50 mL of water were added and the pH was adjusted to pH-4.5 with 1 NHC1. Product precipitation was (II) seen and isolated by filtration. The filtered solid was washed with 100 mL of H.O.The washed solid was dried in a vacuum COOH oven for 14h at 50° C. 6.55g of raw product were obtained Auo and recrystallised with a mixture of isopropanol-water at 90%. The recrystallised solid was dried in a vacuum oven at FHCO 50° C. 6.15g of Roflumilast were obtained (yield 79%). 0085. The X-ray diffraction diagram is consistent with that of Example 3. with an activating agent selected, respectively, from Example 7 (a) carbonyldiimidazole (CDI), (b) 1,1'-carbonyl di-(1,2,4-triazol) (CDT), (c) 1.1'-carbonyl-bis-(2- Preparation of roflumilast (I) methylimdazole), (d) 1.1'-carbonyl-dipiperidin, (e) N,N'-dicyclohexylcarbodiimide (DCC), (f) N,N'- Preparation of (3-(cyclopropylmethoxy)-4-(difluo diisopropylcarbodiimide (DIC), (g) 1-ethyl-3-(3- romethoxy)-phenyl)(1H-imidazol-1-yl)-methanone dimethylaminopropyl)carbodiimide (EDC) and a (IVa) combination of one of the previous with (h) N-hy I0086 32 mL of DMSO were added to 4.0 g of 3-(cyclo droxysuccinimide or (i) N-hydroxyphthalimide in propylmethoxy)-4-(difluoromethoxy)-benzoic acid (II) and an adequate solvent, 3.02 g of CDI (1.2 eq). The mixture was stirred for 2 hours at and, optionally room temperature. A solution of (3-(cyclopropylmethoxy)-4- (difluoromethoxy)-phenyl)(1H-imidazol-1-yl)-methanone ii) isolation of the compound of formula (IV). (IVa) in DMSO was obtained. 2. The process according to claim 1, wherein the activating agent is selected from (a) carbonyldiimidazole (CDI), (b) Formation of Roflumilast: 1,1-carbonyl-di-(1,2,4-triazol) (CDT) and (c) 1.1'-carbonyl I0087 2.78g of 3,5-dichloropyridin-4-amine (III) and 6.59 bis-(2-methylimidazole). g of CsF were loaded over a solution of (3-(cyclopropyl methoxy)-4-(difluoromethoxy)-phenyl)(1H-imidazol-1-yl)- 3. The process according to claim 1, wherein the activating methanone (IVa) in DMSO, at room temperature. The mix agent is (a) carbonyldiimidazole (CDI). ture was heated at 90° C. and left at this temperature for 6 h. 4. The process according to claim 1, wherein the activating After the reaction was completed, 100 mL of water were agent is (b) 1, 1'-carbonyl-di-(1,2,4-triazol) (CDT). added and the pH was adjusted to 6.0 with 1 NHC1. Product precipitation was seen and isolated by filtration. The filtered 5. The process according to claim 1, wherein the solvent of solid was washed with 100 mL of H.O.The washed solid was step dried in a vacuum oven for 14h at 50° C. (i) is selected from dimethylsulphoxide, dimethylforma 0088 5.30 g of raw product were obtained and recrystal mide, dimethylacetamide, tetrahydrofuran, methyl-tet lised with a mixture of isopropanol-water 90%. The recrys rahydrofuran, acetone, methyl ethyl ketone, methyl tallised solid was dried in a vacuum oven at 50° C. 4.35 g of Roflumilast were obtained (yield 70%). isobutyl ketone, dichloromethane, and mixtures thereof. 0089. The X-ray diffraction diagram is consistent with 6. The process according to claim 1, wherein the solvent of that of Example 3. step 1. A process for preparing a compound of formula (IV): (i) is selected from tetrahydrofuran, dimethylsulphoxide and mixtures thereof. (IV) 7. The process according to claim 1, wherein the solvent of step A-N-1, (i) is dimethylsulphoxide. 8. Use of the compounds of formula (IV) for the prepara FHCO tion of the compound Roflumilast. 9. A Process for the preparation of Roflumilast (I): US 2015/0246884 A1 Sep. 3, 2015 10

in the presence of an inorganic base selected among Ci (I) alkali hydroxides, alkali carbonates and alkali fluo 1. rides, in an adequate solvent, and, optionally, in the O 21 presence of a drying agent, O wherein steps (i) and (ii) are defined as in claim 1. Au Cr'sH N 10. The process according to claim 9, wherein the propor Ci tion of the compound of formula (III) ranges from 1 to 1.5 FHCO equivalents with respect to the compound of formula (II). Roflumiiast 11. The process according to claim 9, wherein the alkali hydroxides are selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and . comprising: 12. The process according to claim 9, wherein the alkali i) activation of a compound of formula (II): carbonates are selected from potassium carbonate and cae sium carbonate. (II) 13. The process according to claim 9, wherein the alkali fluoride is caesium fluoride. Auo COOH 14. The process according to claim 9, wherein the inor ganic base is sodium hydroxide or caesium carbonate, in the presence of a drying agent, or caesium fluoride. FHCO 15. The process according to claim 9, wherein the inor ganic base is caesium fluoride. with an activating agent selected from (a) carbonyldi 16. The process according to claim 9, wherein the solvent imidazole (CDI), (b) 1.1'-carbonyl-di-(1,2,4-triazol) in step (iii) is selected from dimethylsulphoxide, dimethyl (CDT), (c) 1.1'-carbonyl-bis-(2-methylimidazole), formamide, dimethylacetamide, tetrahydrofuran, methyl-tet (d) 1.1'-carbonyl-dipiperidin, (e) N,N'-dicyclohexyl rahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl carbodiimide (DCC), (f) N,N'-diisopropylcarbodiim ide (DIC), (g) 1-ethyl-3-(3-dimethylaminopropyl) ketone, dichloromethane, and mixtures thereof. carbodiimide (EDC) and a combination of one of the 17. The process according to claim 16, wherein the solvent previous with (h) N-hydroxysuccinimide or (i) N-hy is dimethylsulphoxide. droxyphthalimide in an adequate solvent, to give an 18. The process according to claim 9, wherein the drying activated compound of (II), of general formula (IV): agent is selected from magnesium sulphate and sodium sul phate. 19. A compound of general formula (IV): (IV) A-s-s-s (IV) FHCO ^-s-s-s where L is, respectively, (a) 1H-imidazol-1-yl, (b) 1H-1, FHCO 2.4-triazol-1-yl, (c) 2-methyl-1H-imidazole-1-yl, (d) piperidin-1-yl, (e) N.N'-dicyclohexylcarbamimidoy loxi, (f) N,N'-diisopropylcarbamimidoyloxi, (g) N'- where L is (a) 1H-imidazol-1-yl, (b) 1H-1,2,4-triazol-1-yl, (3-(dimethylamino)propyl)-N-ethylcarbamimidoy (c) 2-methyl-1H-imidazol-1-yl, (d) piperidin-1-yl. (h) loxy, (h) 2,5-dioxopyrrolidin-1-yloxy or (i) 1,3- 2,5-dioxopyrrolidin-1-yloxy or (i) 1,3-dioxoisoindolin dioxoisoindolin-2-yloxy: 2-yloxy. ii) optionally, isolation of the compound of formula 20. The compound according to claim 19, wherein L is (a) (IV); and 1H-imidazol-1-yl, of formula (IVa): iii) reaction of the compound of formula (IV) with 3.5- dichloropyridin-4-amine of formula (III), (IVa) (III) Auo C Cl FHCO

21. The compound according to claim 19, wherein L is (a) 1H-1,2,4-triazol-1-yl, of formula (IVb): US 2015/0246884 A1 Sep. 3, 2015 11

(IVb)