EP0898564A1 - Method of preparing phosphodiesterase iv inhibitors - Google Patents
Method of preparing phosphodiesterase iv inhibitorsInfo
- Publication number
- EP0898564A1 EP0898564A1 EP97920379A EP97920379A EP0898564A1 EP 0898564 A1 EP0898564 A1 EP 0898564A1 EP 97920379 A EP97920379 A EP 97920379A EP 97920379 A EP97920379 A EP 97920379A EP 0898564 A1 EP0898564 A1 EP 0898564A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- phenyl
- alkenyl
- inhibitors
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/32—Sulfur atoms
- C07D213/34—Sulfur atoms to which a second hetero atom is attached
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
Definitions
- the starting material, 2 is obtained according to the following reaction scheme:
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
A process for the preparation of a compound of structural formula (1) wherein R1 is alkyl, alkenyl, phenyl or substituted phenyl, which comprises the addition of R1 to an intermediate (2): b y treatment of (2) with (R1)3M followed by reductive removal of the sulfinyl group.
Description
TITLE OF THE INVENTION
METHOD OF PREPARING PHOSPHODIESTERASE IV INHIBITORS
BACKGROUND OF THE INVENTION This application is directed to an improved process for making phosphodiesterase IV inhibitors such as those described in WO 94/14742, published July 7, 1994.
Many hormones and neurotransmitters modulate tissue function by elevating intra-cellular levels of adenosine 3', 5'-cyclic monophosphate (cAMP). The role of cyclic AMP (cAMP) as a second messenger is well recognized. It is responsible for transducing the effects of a variety of extracellular signals, including hormones and neurotransmitters. The level of intracellular cAMP is regulated through both its synthesis by adenyl cyclases and degradation by cyclic nucleotide phosphodiesterases (PDE). PDEs form a family of at least seven enzyme isotypes (I-VII) which differ in their affinity for cAMP and/or cGMP, subcellular localisation and regulation (Beavo J.A. and Reifsnyder D.H. (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 rationalised 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, (1986) Mol Pharmacol. 29 506-514; Gillespie P.G. and Beavo J. (1989) Mol. Pharmacol. 36 773-781). The anti-depressant drug, rolipram functions as a selective PDE IV inhibitor. (Schneider H.H. et al, (1986) Eur. J. Pharmacol. 127 105-115.).
The availability of PDE isotype selective inhibitors has enabled the role of PDEs in a variety of cell types to be investigated. In particular it has been established that PDE IV controls the breakdown of cAMP in many inflammatory cells, for example, basophils (Peachell P.T. 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 the inhibition of cell activation. Consequendy PDE IV inhibitors are currently being developed as
potential anti-inflammatory drugs particularly for the prophylaxis and treatment of asthma.
A prior art process for preparing compound I is as shown in the following reaction scheme:
Cp = cyclopentyl pTSA
(±) (E.Z) chromatography
(+) and (-) enantiomers
This process, involving resolution into the enantiomers as a last step necessarily means a commercially unacceptable yield of product.
Another prior art process employs a synthetic strategy using 2S-bornane-010,2-sultan as a chiral auxiliary as shown below:
This method is not amenable to scale-up because of: the high price of the sultam; b) facile isomerization of the acid chloride
during its preparation and/or the coupling reaction with the sultam, and c) extreme odor problem during the sultam cleavage using ethanethiol. Now, with the present invention there is provided a chiral synthesis that produces Compound 1 in high yield and high enantiomeric excess.
SUMMARY OF THE INVENTION
This invention is concerned with a novel process for the preparation of a compound of structural formula I
wherein Rl is phenyl, substituted phenyl, Cl-6 alkyl or C2-6 alkenyl which is an important antiasthmatic agent which comprises the key step of the addition of Rl to an intermediate 2:
by treatment of 2 with (Rl)3M followed by reductive removal of the sulfinyl group.
DETAILED DESCRIPTION OF THE INVENTION
The novel process of this invention is depicted as follows:
wherein: Rl is Cl-6 alkyl, C2-6 alkenyl, phenyl, either unsubstituted or substituted with one or two substituents, which can be the same or different, selected from the group consisting of R2 and Alk(R2)m; wherein
3)-N02,
4)-CN,
5)-OR3,
6)-C3-6 cycloalkoxy,
7)-CO(R3),
8)-COOR3, 9)-SR3,
17)-NHCOR3 or
18)-NHCOOR3; wherein
Alk is straight or branched chain Cl-6 alkylene, C2-6 alkenylene or
C2-6 alkynylene, optionally interrupted by one, two or three -O-, -S-, -S(0)p or -N(R3)-;
R3 is hydrogen or Cl-6 alkyl or C2-6 alkenyl;
R4 is l) C3-6 cycloalkyl,
2) Cl-6 alkyl, or
3) Cl-6 alkenyl; R5 is 1) halo,
2) CF3
3) Cl-3 alkyl, or
4) Cl-3 alkoxy R6 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.
The process comprises treating the olefin 2, and a catalyst, nickel acetylacetonate, Ni(acac)2, in an ethereal solvent such as THF, diethyl ether, glyne, or diglyme, preferably THF cooling to about -35 to - 15°C and adding a slurry of the zincate, RI3M, in the same ethereal solvent also at -35 to -15°C while maintaining the temperature below about -15°C. After aging for 20 to 30 hours the mixture is quenched with ammonium chloride solution and ethyl acetate and the pH adjusted to about 10 with a base, such as ammonium hydroxide, sodium or potassium hydroxide, a 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 acid, pivalic acid, trifluoroacetic chloroacetic acid, or propionic acid and treated with Zn metal. After quenching with water, an immiscible organic solvent such as methylene chloride, chloroform toluene, or ethylacetate 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:
methyl—
>90%
2d
1 diastereomer
Complete details for preparation of 2 are provided in the Example that follows.
In this application "alkyl" means straight or branched alkyl with the indicated number of carbon atoms. "Halo" means chloro, bromo, fluoro or iodo.
EXAMPLE
Synthesis of tolylsulfinyl picoline 2b
Materials Amount MW(d) mmoles
4-picoline 30 mL 93.13(.957) 306 n-BuLi 159 mL 1 ,6M(Hexanes) 255
Menthyltoluene Sulfinate 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 the intenral temperature -45°C. The deep orange reacion mixture was warmed to ambient temperature and aged for 1 hr. The resulting dark solution was treated at 22°C with a solution of the sulfinate in THF (120mL) while maintaining the temperature <27°C. The reaction was aged for 30 min upon which time HPLC analysis indicated disappearance of the sulfinate 2a. The reaction mixture was quenced with IM aqueous NH4CI (700mL), CH2CI2 (lOOOmL) was added and the layers were partitioned. The organic layer was dried over Na2Sθ4 and concentrated in vacuo. The residue was flushed twice with hexane (2x200mL) and then swished with hexanes (220mL, 9mL/g based on theoretical yield) to produce a thick white slurry which was aged overnight. The mixture was filtered, the cake was washed with hexanes (50mL) and dried in vacuo at 38°C to afford 21.46 g of the product (91%).
Synthesis of Aldol Adduct 2d
Materials Amount MW mmoles
Cyclopentylisovaniline 2c 22.44g 220 102 tolylsulfinyl picoline 2b 21.46 231 93 t-amyl ONa 12.3g 110 112
A heterogeneous mixture of the aldehyde and sulfoxide in THF (235mL) was cooled to -15°C and treated with solid t-amylONa which resulted in a temperature increase to -8°C. HPLC analysis [sample must be quenched into a mixture of CH3CN/lN-NH4θ(aq) to avoid the retro-aldol reaction which occurs in aqueous base] indicated that the reaction was complete in 15 minutes. The mixture was quenched with NH4Cl(aq) (IM; 600 mL), CH2CI2 (800mL) was added, the layers were partitioned and the organic layer was dried over Na2Sθ4, filtered and concentrated in vacuo. The residue was flushed with heptane (150mL) and then swished with 340 mL of 2: 1 heptane- isopropyl acetate (8mL/g based on theoretical yield) for 3 hours. The mixture was filtered and the cake was washed with heptane (100 mL) and dried in vacuo at 36°C to afford 38.8 g of product (93%) as a single diastereomer.
Synthesis of Olefin 2
Materials Amount MW mmoles
Sulfoxide-alcohol 2d 38.8g 451 86
Tosylimidazole 22.9g 222.3 103 NaH 5g 24(80% in mineral oil) 215
Imidazole 293mg 68 4.3
A solution of the sulfoxide-alcohol 2d in THF-DMF (3:2, 430mL) was cooled to 0°C and then treated successively with
tosylimidazole, NaH and imidazole. Venting of the reaction vessel was essential to allow for hydrogen evolution. The mixture was aged for 2 hours at which time HPLC analysis shows that <2% of starting material remained. The reaction mixture was quenched with H2θ (60mL) partitioned between ethyl acetate (500mL) and H2θ (400mL) and the organic layer dried over Na2S04, filtered and concentrated in vacuo. The residue was suspended in 365 mL of 2:1 heptane - isopropyl acetate and the slurry aged overnight. Filtration, washing with 2: 1 heptane - isopropyl acetate (lOOmL) was drying afforded 24.75g of 2 (66%).
Synthesis of Adduct 4
Materials Amount MW mmoles
2 0.5 g 434 1.15
ZnCl2 4.6 mL 0.5M(THF) 2.3
PhMgBr 2.3 mL 3M(Et2θ) 6.9
Ni(acac)2 20.6 mg 256.91 0.08
PtoZnMgBr
A solution of ZnCl2 in THF (.5M solution) at 0°C was treated with PhMgBr so that the temperture remained below 10°C. The resulting slurry was aged at 0°C for 15 min and at ambient temperature for 10 min. The mixture was then cooled to -25°C.
Addition
A solution of the olefin-2 and Ni(acac)2 in THF (3.5 mL) was cooled to -25°C and treated with the Ph3ZnMgBr slurry from above so that the internal temperature remained -22°C. The mixture was aged at <-27°C for 25 hr upon which time HPLC analysis showed that <4A% of 2 remained. The mixture was quenched with NH4CI (30mL), ethyl acetate (50 mL) was added and the pH was adjusted to about 10 with NH4OH. The organic layer was separated and dried over Na2Sθ4, filtered and concentrated in vacuo. The residue was dissolved in 2.8 mL THF and 0.4 mL acetic acid and treated with Zn metal (160
mg) at ambient temperature. The reaction was aged for 1 hr at 25 °C at which time HPLC analysis indicated complete consumption of starting material. The reaction mixture was quenched with H2θ, CH2CI2 was added and the pH adjusted to about 6 to produce two clear layers. [HPLC analysis indicated minimal losses of product in the aqueous layer.] The organic layer was dried over Na2S04, filtered and concentrated in vacuo. Chromatography (1: 1 hexane - ethyl acetate) afforded 1 (62%). Chiral HPLC analysis indicated a 92% enantiomeric excess (ee).
Claims
1. A process for the preparation of a compound of structural formula I:
1 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°C followed by treatment with a zincate of formula RI3M 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: Rl i is Cl-6 alkyl, C2-6 alkenyl, phenyl, either unsubstituted or substituted with one or two substituents, which can be the same or different, selected from the group consisting of R2 and Alkl(R2)m wherein
3)-N02,
4)-CN,
5)-OR3,
6)-C3-6 cycloalkoxy,
7)-CO(R3),
8)-COOR3,
9)-SR3,
17)-NHCOR3 or 18)-NHCOOR3; wherein Alk is straight or branched chain Cl-6 alkylene, C2-6 alkenylene or
C2-6 alkynylene, optionally interrupted by one, two or three
-O-, -S-, -S(0)p or -N-(R3)-; R3 is hydrogen or Cl-6 alkyl or C2-6 alkenyl;
R4 is 1) C3-6 cycloalkyl,
2) Cl-6 alkyl, or 3) Cl-6 alkenyl;
R5 is 1) halo,
2) CF3
3) Cl-3 alkyl, or
4) Cl-3 alkoxy R6 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 Rl is phenyl.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1568796P | 1996-04-17 | 1996-04-17 | |
US15687 | 1996-04-17 | ||
GB9612083 | 1996-06-10 | ||
GBGB9612083.7A GB9612083D0 (en) | 1996-06-10 | 1996-06-10 | Method of preparing phosphodiesterase IV inhibitors |
PCT/US1997/006131 WO1997038976A1 (en) | 1996-04-17 | 1997-04-14 | Method of preparing phosphodiesterase iv inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0898564A1 true EP0898564A1 (en) | 1999-03-03 |
Family
ID=26309476
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97920379A Withdrawn EP0898564A1 (en) | 1996-04-17 | 1997-04-14 | Method of preparing phosphodiesterase iv inhibitors |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP0898564A1 (en) |
CN (1) | CN1216532A (en) |
AR (1) | AR006550A1 (en) |
AU (1) | AU2459297A (en) |
BR (1) | BR9708684A (en) |
CZ (1) | CZ333298A3 (en) |
EA (1) | EA000877B1 (en) |
SK (1) | SK143198A3 (en) |
TW (1) | TW426669B (en) |
WO (1) | WO1997038976A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0931066B1 (en) * | 1996-09-17 | 2002-05-15 | Merck & Co., Inc. | Method of preparing phosphodiesterase iv inhibitors |
TW508353B (en) * | 1996-09-17 | 2002-11-01 | Merck & Co Inc | Method of preparing phosphodiesterase IV inhibitors |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW263495B (en) * | 1992-12-23 | 1995-11-21 | Celltech Ltd | |
GB9326173D0 (en) * | 1993-12-22 | 1994-02-23 | Celltech Ltd | Chemical compounds and process |
-
1997
- 1997-04-07 AR ARP970101372A patent/AR006550A1/en unknown
- 1997-04-14 BR BR9708684A patent/BR9708684A/en unknown
- 1997-04-14 AU AU24592/97A patent/AU2459297A/en not_active Abandoned
- 1997-04-14 WO PCT/US1997/006131 patent/WO1997038976A1/en not_active Application Discontinuation
- 1997-04-14 CN CN97193932A patent/CN1216532A/en active Pending
- 1997-04-14 SK SK1431-98A patent/SK143198A3/en unknown
- 1997-04-14 EA EA199800931A patent/EA000877B1/en not_active IP Right Cessation
- 1997-04-14 CZ CZ983332A patent/CZ333298A3/en unknown
- 1997-04-14 EP EP97920379A patent/EP0898564A1/en not_active Withdrawn
- 1997-04-15 TW TW086104869A patent/TW426669B/en not_active IP Right Cessation
Non-Patent Citations (1)
Title |
---|
See references of WO9738976A1 * |
Also Published As
Publication number | Publication date |
---|---|
CN1216532A (en) | 1999-05-12 |
TW426669B (en) | 2001-03-21 |
WO1997038976A1 (en) | 1997-10-23 |
BR9708684A (en) | 1999-08-03 |
EA199800931A1 (en) | 1999-04-29 |
AR006550A1 (en) | 1999-09-08 |
AU2459297A (en) | 1997-11-07 |
EA000877B1 (en) | 2000-06-26 |
SK143198A3 (en) | 1999-06-11 |
CZ333298A3 (en) | 1999-03-17 |
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