EA000877B1 - Method of preparing phosphodiesterase iv inhibitors - Google Patents

Abstract

1. A process for the preparation of a compound of structural formula I: which comprises the steps of: 1) treating a compound of structural formula 2: with a catalyst, Ni(acac)2, in a ethereal solvent at -35 to -15 degree C followed by treatment with a zincate of formula R<1>3M and aging for 20-30 hours to produce the adduct 4 2) treating the adduct 4 in an ethereal solvent and an organic acid with Zn metal to produce the product, 1, wherein: R<1> is C1-C6 alkyl, C2-C6 alkenyl, phenyl, either unsubstituted or substituted with one or two substituents, which can be the same or different, selected from the group consisting of R<2> and Alkl(R<2>)m wherein R<2> is 1)halo, 2)-N(R<3>)2, 3)-N02, 4)-CN, 5)-OR<3>, 6)-C3-C6 cycloalkoxy, 7)-CO(R<3>), 8)-COOR<3>, 9)-SR<3>, 10)-SO3H, 11)-SO2(R<3>), 12)-SO2N(R<3>)2, 13)-CON(R<3>)2, 14)-NHSO2R<3>, 15)-N(SO2R<3>)2, 16)-NHSO2N(R<3>)2, 17)-NHCOR<3> or 18)-NHCOOR<3>; wherein Alk is straight or branched chain Cl -6 alkylene, C2-6 alkenylene or C2-C6 alkynylene, optionally interrupted by one, two or three -O-, -S-, -S(O)p or -N-(R<3>)-; R<3> is hydrogen or C1-C6 alkyl or C2-C6 alkenyl; R<4> is 1) C3-C6 cycloalkyl, 2) C1-C6 alkyl, or 3) C1-C6 alkenyl; R<5> is 1) halo, 2) CF3 3) C1-C3 alkyl, or 4) C1-C3 alkoxy R<6> is 1) tolyl, 2) phenyl, 3) t-butyl, or 4) mesityl; M is ZnLi or ZnMgBr. m is zero or an integer selected from 1, 2 and 3; and p is an integer selected from 1 and 2. 2. The process of claim 1 wherein M is ZnMgBr. 3. The process of claim 2, wherein R<1> is phenyl.

Description

BACKGROUND OF THE INVENTION

This application is directed to an improved process for the preparation of phosphodiesterase IV inhibitors, such as those described in WO 94/14742, published July 7, 1994.

Many hormones and neurotransmitters modulate tissue function by increasing intracellular levels of adenosine-3 ', 5'-cyclic monophosphate (cAMP). The role of cyclic AMP (cAMP) as a secondary messenger is well known. He is responsible for the transduction of the effects of a variety of extracellular signals, including hormones and neurotransmitters. The content of intracellular cAMP is regulated both by its synthesis by adenylcyclases and by decomposition by cyclic nucleotide phosphodiesterases (PDE). PDEs form a family of at least seven enzyme isotypes (I-VII) that differ in their affinity for cAMP and / or cGMP, subcellular localization and regulation (Beavo JA and Reifsnyder DH (1990) Trends Pharmacol. Sci. 11 150- 155; Conti M. et al., (1991) Endocrine Rev. 12 218-234). The clinical effects of a number of drugs can be streamlined based on their selectivity for a particular PDE isotype. For example, cardiotonic drugs milrinone and zaprinast are inhibitors of PDE III and PDE V, respectively. (Harrison S.A. et al., (1986) Mol. Pharmacol. 29 506-514; Gillespie P. G. and Beavo J. (1989) Mol. Pharmacol. 36 773-781). The antidepressant rolipram acts as a selective PDE IV inhibitor. (Schneider, N.N. et al., (1986) Eur. J. Pharmacol. 127 105-115).

The availability of selective PDE isotype inhibitors made it possible to study the role of PDE in different cell types. In particular, it was found that PDE IV regulates the decomposition of cAMP in many inflammatory cells, for example, basophils (Peachell P.T. et al., (1992) J. Inununol. 148 2503-2510) and eosinophils (Dent G. et al. , (1991) Br. J. Pharmacol. 103 1339-1346), and that inhibition of this isotype is associated with inhibition of cellular activation. Therefore, PDE IV inhibitors are currently being developed as potential anti-inflammatory drugs, in particular for the prevention and treatment of asthma.

The previously known method for producing compound I is shown in the following reaction scheme:

This method, including the separation of enantiomers as the last step, certainly means an industrially unacceptable yield.

Another previously known method uses a synthesis strategy using 2Sbornan-01 of 0,2-sultam as a chiral adjuvant, as shown below

This method is not acceptable for increasing the scale of production due to a) the high price of sultam; c) easy isomerization of the acid chloride during its preparation and / or coupling reaction with sultam; and c) problems of an extremely strong odor during the removal of sultam using enantiol.

Currently, thanks to this invention, chiral synthesis is provided which provides compound 1 in high yield and high enantiomeric excess.

SUMMARY OF THE INVENTION

This invention relates to a new method for producing compounds of structural formula 1

where R ¹ denotes phenyl, substituted phenyl, C _1-6 alkyl or C _2-6 alkenyl, which is an important anti-asthma agent, which includes a key step of attaching R ¹ to intermediate 2:

by treating compound 2 with compound (R ¹ ) ₃ M followed by reductive reduction of the sulfinyl group.

DETAILED DESCRIPTION OF THE INVENTION

The new method of the present invention is described as follows:

Where

R ¹ is C _1-6 alkyl, C _2-6 alkenyl, phenyl unsubstituted or substituted with one or two substituents, which may be the same or different, selected from the group consisting of R ² and Alk (R ² ) m, where

R ² is

1) halogen

2) -N (R ³ ) 2,

3) -no ₂ ,

4) -CN,

5) -OR ³ ,

6) -C3-6 cycloalkoxy,

7) -CO (R ³ ),

8) -COOR ³ ,

9) -SR ³ ,

10) -BO3H,

11) -SO2 (R ³ ),

12) -SO ₂ N (R ³ ) ₂

13) -CON (R ³ ) ₂ ,

14) -nhso ₂ r ³ ,

15) -N (SO ₂ R ³ ) ₂ ,

16) -nhso ₂ (r ³ ) ₂

17) -NHCOR ³ or

18) -NHCOOR ³ , where

Alk is straight or branched C _1-6 alkylene, C _2-6 alkenyl en or C _2-6 alkynylene, optionally interrupted by one, two or three groups —O—, —S—, —S (O) _p or —N ( R ³ ) -;

R ³ is hydrogen or C _1-6 alkyl or C _2-6 alkenyl;

R ⁴ is

1) C _3-6 cycloalkyl,

2) C _1-6 alkyl or

3) C _1-6 alkenyl;

R ⁵ is

1) halogen

2) СFз,

3) C _1-3 alkyl or

4) C _1-3 alkoxy;

R ⁶ is

1) tolyl

2) phenyl,

3) tert-butyl or

4) mesityl;

M is ZnLi or ZnMgBr; m is zero or an integer selected from 1, 2 and 3; and p is an integer selected from 1 and 2.

The method includes treating olefin 2 and a catalyst, nickel acetylacetonate,

Ni (acac) 2, in an ether solvent such as THF (tetrahydrofuran), diethyl ether, glycol or diglyme, preferably THF, cooling to about -35 to -15 ° C and adding a suspension of zincate, (R ¹ ) ₃ M in the same ether solvent also at -35 to -15 ° C while maintaining the temperature below about -15 ° C. After standing for 20-30 hours, the mixture is quenched with a solution of ammonium chloride and ethyl acetate and the pH is adjusted to about 10 with a base such as ammonium hydroxide, sodium or potassium hydroxide, sodium or potassium carbonate. Product 4 is isolated from the organic layer, dissolved in an ether solvent, preferably THF, and an organic acid such as acetic acid, pivalic acid, trifluoroacetic, chloroacetic acid or propionic acid and treated with zinc metal. After quenching the reaction with water, an immiscible organic solvent such as methylene chloride, chloroform, toluene or ethyl acetate is added and the pH is adjusted to about 6. Product 1 is isolated from the organic layer.

Starting material 2 is prepared according to the following reaction scheme:

All details of the preparation of compound 2 are presented in the following example.

In this application, alkyl is straight or branched alkyl with the indicated number of carbon atoms. Halogen means chlorine, bromine, fluorine or iodine.

Example.

Synthesis of Tolylsulfinyl Picolin 2b

Materials number Like mass (d) mmol 4-picoline 30 ml 93.13 (957) 306 n-BuLi 159 ml 1.6M (hexanes) 255 Mentyltoluenesulfinate 2a 30 g 294.46 102

A solution of picoline in THF (351 ml) was cooled to -50 ° C and treated with n-BuLi while maintaining an internal temperature of -45 ° C. The dark orange reaction mixture was warmed to ambient temperature and kept for 1 h. The resulting dark solution was treated at 22 ° С with a solution of sulfinate in THF (1 20 ml) while maintaining the temperature <27 ° С. The reaction mixture was aged for 30 minutes, after which an analysis of HPLC showed the disappearance of sulfinate 2a. The reaction mixture was quenched with a 1M aqueous solution of NH ₄ Cl (700 ml), CH ₂ Cl ₂ (1000 ml) was added, and the layers were separated. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was washed twice with hexane (2x200 ml) and then separated with hexanes (220 ml, 9 ml / g based on theoretical yield), giving a thick white suspension, which remained overnight. The mixture was filtered, the filter cake was washed with hexanes (50 ml) and dried in vacuum at 38 ° C, giving 21.46 g of product (91%).

Synthesis of aldol adduct 2d

Materials number Mol.mas. mmol Cyclopentylaniline 2 s 22.44 g 220 102 Tolylsulfinyl-picoline 2b 21.46 231 93 Tert-amyl ONa 12.3 g 110 112

A heterogeneous mixture of aldehyde and sulfoxide in THF (235 ml) was cooled to -15 ° C and treated with solid tert-amyl-ONa, resulting in a temperature increase of -8 ° C. HPLC analysis [the sample had to be quenched in a mixture of CH ^^^. -KIDO (aq.) To avoid the retroaldol reaction that occurs in the water base] indicates that the reaction was completed in 1 5 min. The mixture was quenched with NH ₄ Cl (aq) (1M; 600 ml), CH ₂ Cl ₂ (800 ml) was added, the layers were separated and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was washed with heptane (150 ml), and then 340 ml of a 2: 1 mixture of heptane-isopropyl acetate (8 ml / g based on theoretical yield) was added and the mixture was left for 3 hours. The mixture was filtered and the filter cake was washed with heptane (100 ml ) and dried in vacuum at 36 ° C, giving 38.8 g of product (93%) as a single diastereomer.

Olefin Synthesis 2

Materials If- honor Mol.massa mmol Sulfoxide-alcohol 2d 38.8 g 451 86 Tosilimidazole 22.9 g 222.3 103 NaH 5 g 24 (80% in mineral oil) 215 Imidazole 293 mg 68 4.3

A solution of sulfoxide-alcohol 2d in THF-DMF (3: 2, 430 ml) was cooled to 0 ° C and then treated sequentially with tosilimidazole, NaH and imidazole. Effective gas was removed from the reaction vessel to ensure hydrogen evolution. The mixture was aged for 2 hours, during which time HPLC analysis showed that <2% of the starting material remained. The reaction mixture was quenched with H ₂ O (60 mL), partitioned between ethyl acetate (500 mL) and H ₂ O (400 mL) and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was suspended in 365 ml of a 2: 1 heptane-isopropyl acetate mixture, and the suspension was left overnight. Filtration, washing with a 2: 1 mixture of heptane-isopropyl acetate (100 ml) and drying gave 24.75 g of compound 2 (66%).

Synthesis of adduct 4

Materials number Mol.mass mmol 2 0.5 g 434 1.15 ZnCl2 4.6 ml 0.5M (THF) 2,3 Phmgbr 2.3 ml 3M (Et2O) 6.9 Ni (acac) 2 20.6 mg 256.91 0.08 PhzZnMgBr

A solution of ZnCl ₂ in THF (0.5 M solution) at 0 ° C was treated with PhMgBr so that the temperature remained below 10 ° C. The resulting suspension was kept at 0 ° C for 1 5 min and at ambient temperature for 10 min. Then the mixture was cooled to -25 ° C.

Joining.

A solution of olefin-2 and Ni (acac) 2 in THF (3.5 ml) was cooled to -25 ° C and treated with the above suspension of Ph ₃ ZnMgBr so that the internal temperature remained -22 ° C. The mixture was kept at <-27 ° C for 25 hours, after which an HPLC analysis showed that <4A% of compound 2 remained. The mixture was quenched with NH ₄ Cl (30 ml), ethyl acetate (50 ml) was added, and the pH was adjusted to about 1 0 using NH4OH. The organic layer was separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in 2.8 ml of THF and 0.4 ml of acetic acid and treated with Zn metal (1 60 mg) at ambient temperature. The reaction mixture was aged for 1 h at 25 ° C; HPLC analysis showed the complete consumption of the starting material. The reaction was quenched with H2O, CH2Cl2 was added, and the pH was adjusted to about 6, giving two distinct layers. [HPLC analysis showed minimal product loss in the aqueous layer]. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (1: 1 hexane-ethyl acetate) gave compound 1 (62%). Chiral HPLC analysis showed an enantiomeric excess of 92% (s).

Claims (18)

CLAIM 1. A method of obtaining a compound of structural formula 1 which comprises the steps of: 1) treating the compound of structural formula 2 with a catalyst, Ni (acac) 2, in a simple ether solvent at -35 - -15 ° C, followed by treatment with zincate of the formula R ¹ 3M and holding for 20-30 hours to obtain adduct 4 2) processing the adduct 4 in a simple ether solvent and organic acid with metallic Zn to obtain product 1, where R ¹ is C1- ^ kkt, C2-6 alkenyl, phenyl unsubstituted or substituted by one or two substituents, which may be the same or different, selected from the group consisting of R ² and Alk (R ² ) m, where R ² is 1) halogen 2) -N (R ³ ) 2, 3) -NO2, 4) -CN, 5) -OR ³ , 6) -C3-6cycloalkoxy, 7) -CO (R ³ ), 8) -COOR ³ , 9) -SR ³ , 10) ^ O3H, 11) -SO2 (R ³ ), 12) -SO 2 N (R ³ ) 2, 13) -CON (R ³ ) 2, 14) -NHSO ₂ R ³ , 15) -N (SO2R ³ ) 2, 16) -NHSO ₂ N (R ³ ) ₂ , 17) -NHCOR ³ or 18) -NHCOOR ³ ; where Alk denotes a straight or branched C1 _-6 alkylene, _C2-6 alkenylene or C _2-6 alkynylene, optionally interrupted by one, two or three groups, —O—, —S—, —S (O) _p or —N- (R ³ ) -; R ³ is hydrogen or P ^ lkyl or C2-6 alkenyl; R ⁴ is 1) C _3-6 cycloalkyl, 2) C ^ alkyl or 3) C1-6 alkenyl; R ⁵ is 1) halogen 2) СFз, 3) C1 -3alkyl or 4) A ^ alkoxy; R ⁶ is 1) tolyl 2) phenyl, 3) tert-butyl or 4) mesityl; M is ZnLi or ZnMgBr; m is zero or an integer selected from 1, 2 and 3; and p is an integer selected from 1 and 2. 2. The method according to claim 1, where M denotes ZnMgBr. 3. The method according to claim 2, where R ¹ denotes phenyl.