SK143198A3 - Method of preparing phosphodiesterase iv inhibitors - Google Patents

Abstract

A process for the preparation of a compound of structural formula (1) wherein R<1> is alkyl, alkenyl, phenyl or substituted phenyl, which comprises the addition of R<1> to an intermediate 2: by treatment of 2 with (R<1>)3M followed by reductive removal of the sulfinyl group.

Description

Technical field

The invention relates to an improved process for the production of phosphodiesterase IV inhibitors as described, for example, in WO 94/14742, published July 7, 1994.

BACKGROUND OF THE INVENTION

Many hormones and neurotransmitters modulate tissue function by increasing the intracellular level of adenosine 3 ‘, 5‘-cyclic monophosphate (cAMP). The role of cyclic AMP (cAMP) as a second messenger is well known. It is responsible for transducing the effects of a number of extracellular signals, including hormones and neurotransmitters. The level of intracellular cAMP is regulated through its synthesis by adenylcyclase as well as degradation by cyclic nucleotide phosphodiesterases (PDE). PDEs consist of a group of at least seven enzyme isotypes (1-VII), which 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. 72 218-234). The clinical effects of a number of drugs can be assessed on the basis of their selectivity for a particular PDE isotype. For example, the cardiotonic drugs milrinone and zaprinast are PDE III and PDE V inhibitors (respectively). (Harrison S.A. et al. (1989) Mol Pharmacol. 29,506-514; Gillespie P.G. and Beavo J. (1989) Mol. Pharmacol. 36,773-781). Rolipram has the function of a selective PDE IV inhibitor. (Schneider H. H. et al. (1986) Eur. J. Pharmacol. 127 105-115).

The utility of selective PDE isotypes has prompted research into the role of PDE in various cell types. For example, PDE IV has been found to control cAMP cleavage in many inflammatory cells, such as basophils (Peachell PT et al. (1992) J. Immunol. 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

-2-cell activation. As a result, PDE IV inhibitors are currently being developed for use as anti-inflammatory drugs, particularly for the prophylaxis and treatment of asthma.

The prior art process for the preparation of compound 1 is illustrated in the following reaction scheme:

(±)

OC _p (E, Z)

I chromatography, _x .

The ((+) and (-) enantiomers

However, this process, including resolution to enantiomers in the last step, does not provide a commercially usable amount of yield.

Another known synthesis method using 2S-borane-010,2sultam as a chiral auxiliary can be illustrated as follows:

OMe

CHO

AcOH, piperidine PhMe

SOCI ₂

CH ₂ Cl ₂

-4EtSH, n-BuLi

THF, ° C

1. NaOH aq.

2. HCl aqueous solution pH 5.0

However, this method cannot be applied to a wider extent due to: (a) the high price of sultam; b) easy isomerization of sulfuric acid during the preparation and / or coupling reaction with sultam; (c) a significant odor problem during cleavage of the sultam using ethanethiol.

The present invention provides a chiral synthesis resulting in compound 1 in high yield and high enantiomeric excess.

-5-Summary of the invention

The present invention provides a process for the preparation of a compound of structural formula 1

wherein R ¹ is phenyl, substituted phenyl, alkyl or _Ο ν6 C _{2nd 6} alkenyl, which is an important antiasthmatic agent, comprising the key step of adding R ¹ to intermediate 2:

(2) wherein intermediate 2 is treated with (R ¹ ) ₃ M followed by reductive removal of the sulfinyl group.

The method according to the invention can be illustrated as follows:

OR

R3M

Ni (acac) ₂

THF

-20 H, 10 H

R

R '(1)

where

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

where

R ² is 1) a hydrogen atom,

2) -N (R ³ ) ₂ ,

3) -NO _2l

4) -CN

5) -OR ³

6) -C _{third 6} cycloalkoxy,

(7) -CO (R ³ ),

8) -COOR ³

9) -SR ³

10) -SO ₃ H

(11) -SO ₂ (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 N (R ³ ) ₂ ,

17) ³ or -NHCOR

18) -NHCOOR ^3; where

Alk means a linear or branched chain of C 1-4 alkylene, C ₂ . ₆ alkenylene or

-7C ₂ . ₆ alkenylene, optionally interrupted by one, two or three -O-, -S-, -S (O) _p or -N (R ³ ) -;

R ³ represents a hydrogen atom or C 1-6 alkyl; ₆ alkyl or C _{2nd 6} alkenyl;

R ⁴ is 1) C ₃ . ₆ cycloalkyl,

2) _Ο ν6 alkyl, or

3) _{C 1-6} alkenyl;

R ⁵ is 1) halogen,

2) CF ₃ ;

3) O 1-3 alkyl, or

4) 0, .3 alkoxy,

R ⁶ is 1) totyl,

2) phenyl;

3) t-butyl; or

4) mesityl;

M is ZnLi or ZnMgBr;

m is zero or an integer of 1, 2 and 3;

p is an integer from 1 and 2.

The process comprises treating olefin 2 and a catalyst, nickel acetyloctate, Ni (acac) ₂ , in an ether solvent such as THF, diethyl ether, glyne or diglyme, preferably THF, cooling to -35 ° C to -15 ° C and adding a zinc salt suspension. R ¹ 3 M, in the same ethereal solvent also at -35 DEG C. to -15 DEG C., while maintaining the temperature below about 15 ° C. After maturation for 20 to 30 hours, the mixture is quenched with ammonium chloride solution and ethyl acetate and the pH is adjusted to 10 with a base such as ammonium, sodium or potassium hydroxide or sodium or potassium carbonate. The product 4 is isolated from the organic layer, dissolved in an ethereal solvent, preferably THF, and an organic acid such as acetic, pivalic, trifluoroacetic, chloroacetic or propionic acid and treated with a zinc metal. After quenching 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. The product 1 is isolated from the organic layer.

The starting material 2 is obtained according to the following reaction scheme:

of methyl

ABOUT

^IS, R ⁶

-30 ° C room temperature> 90% (2a)

Ts-lm

NaH

THF-DMF (3: 1) 0 ° C 2h

66%

(2)

Full details of the preparation of material 2 are given in the example below.

In this application, "alkyl" means a linear or branched alkyl having the number of carbon atoms indicated. "Halo" means a chlorine, bromine, fluorine or iodine atom.

Examples of embodiments of the invention

Synthesis of tolylsulfinylpicoline 2b

Materials number Molecular weight (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 maintaining an internal temperature of -45 ° C. The mixture of warm orange was warmed to room temperature and aged for 1 hour. The resulting dark solution was treated at 22 ° C with a solution of sulfinate in THF (120 mL) maintaining a temperature of <27 ° C. The reaction mixture was aged for 30 minutes while HPLC analysis showed the disappearance of sulfinate 2a. The reaction mixture was quenched with 1 M aqueous NH ₄ Cl (700 mL), CH ₂ Cl ₂ (1000 mL) was added and the layers were separated. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was washed twice with hexane (2x200 mL) and treated with a stream of hexanes (220 mL, 9 mL / g - based on theoretical yield) to give a thick white precipitate which was aged overnight. The mixture was filtered, the filter cake was washed with hexanes (50 mL) and dried under vacuum at 38 ° C to give 21.46 g of product (91%).

Synthesis of aldol adduct 2d

Materials number Molecular weight mmol cyclopentylizovanilin 2c 22,44 g 220 102 tolylsulfinyipicoline 2b 21.46 231 93 t-amyl ONa 12.3 g 110 112

The heterogeneous mixture of aldehyde and sulfoxide in THF (235 mL) was cooled to -15 ° C and treated with solid t -amyl ONa, causing the temperature to rise to -8 ° C. HPLC analysis (the sample must be quenched in CH ₃ CN / 1N NH ₄ Cl (aq) to avoid the retro-aldol reaction taking place in the aqueous base) showed that the reaction was complete after 15 minutes. 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 treated with a stream of 340 mL of heptane and isopropyl acetate 2: 1 (8 mL / g - based on theoretical yield) for 3 hours. The mixture was filtered and the filter cake was washed with heptane (100 mL) and dried under vacuum at 36 ° C to give 38.8 g of product (93%) as a simple diastereomer.

Synthesis of olefin 2

Materials number Molecular weight mmol sulfoxide-alcohol 2d 38,8 g 451 86 tosylimidazol 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 subsequently treated with tosylimidazole, NaH and imidazole sequentially. The reaction vessel was vented to allow hydrogen evolution. The mixture was aged for 2 hours, 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 Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was suspended in 365 ml of heptane and isopropyl acetate 2: 1 and the precipitate was aged overnight. After filtration, washing with heptane and isopropyl acetate (100 mL) and drying, 24.75 g of product 2 (66%) was obtained.

-11 Adduct synthesis 4

Materials number Molecular weight mmol 2 0.5 g 434 1.15 ZnCl ₂ 4.6 ml 0.5M (THF) 2.3 PhMgBr 2.3 ml 3M (Et ₂ O) 6.9 Ni (acac) 2 20.6 mg 256,91 0.08

Ph ₃ ZnMgBr

A solution of ZnCl ₂ in THF (0.5M solution) was treated with PhMgBr at 0 ° C while maintaining the temperature above 10 ° C. The resulting precipitate was aged at 0 ° C for 15 minutes and at room temperature for 10 minutes. The mixture was then cooled to -25 ° C.

addition

A solution of olefin-2 and Ni (acac) ₂ in THF (3.5 mL) was cooled to -25 ° C and treated with the above precipitate Ph ₃ ZnMgBr while maintaining an internal temperature of -22 ° C. The mixture was aged at <-27 ° C for 25 hours, whereby HPCL analysis showed that <4A% of product 2 remained. The mixture was quenched with NH ₄ Cl (30 mL), ethyl acetate (50 mL) was added and The pH was adjusted to 10 with NH ₄ OH. The organic layer was separated and dried over Na ₂ SO ₄ , 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 zinc (160 mg) at room temperature. The reaction mixture was aged at 25 ° C for 1 hour, HPCL analysis showed complete consumption of the starting material. The reaction mixture was quenched with H ₂ O, CH ₂ Cl _{2 was added} and the pH was adjusted to 6 to form two distinct layers. (HPCL analysis showed minimal product losses in the aqueous layer.) The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Chromatography (1: 1 hexane-ethyl acetate) gave product 1 (62%). Chiral HPCL analysis showed a 92% excess of enantiomers (ee).

Claims (18)

PATENT CLAIMS A process for the preparation of a compound of structural formula 1 (1), characterized in that it comprises the following steps: 1) treatment of a compound of structural formula 2: with a catalyst, Ni (acac) _2, in an ethereal solvent, for example at -35 to -15 ° C and subsequent treatment with a zinc salt of the formula R ¹ 3M and aging for 20-30 hours to form the adduct 4. 2) treating adduct 4 in an ether solvent and an organic zinc acid to produce product 1, wherein - 13 R ¹ is alkyl, C 2-6 alkenyl, phenyl, unsubstituted or substituted with one or two substituents, which may be identical or different, selected from R ² and Alk (R ²⁾ m; where R ² is 1) halogen, 2) -N (R ³ ) ₂ , 3) -NO _2l 4) -CN 5) -OR ³ 6) -C _{third 6} cycloalkoxy, (7) -CO (R ³ ), 8) -COOR ³ 9) -SR ³ 10) -SO ₃ H (11) -SO ₂ (R ³ ), (12) -SO ₂ N (R ³ ) ₂ , 13) -CON (R ³ ) _2i 14) -NHSO ₂ R ³ 15) -N (SO ₂ R ³ ) ₂ , 16) -NHSO ₂ N (R ³ ) ₂ , 17) ³ or -NHCOR 18) -NHCOOR ^3; where Alk means a linear or branched chain C 1-4 alkylene, C ₂ . ₆ alkenylene or C _{2nd 6} alkenylene, optionally interrupted by one, two or three -O-, -S-, -S (O) _p or -N (R ³ ) -; R ³ represents a hydrogen atom or C 1-6 alkyl; ₆ alkyl or C _{2nd 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) CF ₃ ; - 143) 0. ₃ alkyl, or 4) C ,. ₃ alkoxy, R ⁶ is 1) totyl, 2) phenyl, 3) t-butyl; or 4) mesityl; M is ZnLi or ZnMgBr; m is zero or an integer of 1, 2 or 3; p is an integer of 1 or 2. Method according to claim 1, characterized by. wherein M is ZnMgBr. 3. The method of claim 2, characterized uj whether account is characterized in that R ¹ is phenyl.