阅读说明：本技术 用于合成取代的γ内酰胺的方法 (Process for the synthesis of substituted gamma lactams ) 是由 D·T·迪安 M·E·加斯特 D·W·奥尔德 E·T·斯雅格 B·I·戈林 C·M·朗提尔 于 2013-08-20 设计创作，主要内容包括：本发明提供了用于制备多种明确限定的取代的γ内酰胺的合成方法。可以通过本发明的方法制备的化合物可用于治疗多种病状。在本发明的一些实施方案中,所述化合物可用于治疗例如像青光眼之类的眼部病症、降低升高的眼内压等。在其它实施方案中,所述化合物可用于治疗肠易激病。在另外的实施方案中,所述化合物可用于促进毛发生长。在再另外的实施方案中,所述化合物可用于促进伤口愈合、瘢痕减少等。(In the embodiments of the invention, the compounds are useful for treating ocular disorders such as, for example, glaucoma, lowering elevated intraocular pressure, and the like.)

1, A process for preparing a compound having the general structure (1)

Wherein:

R₁is H, C₁-C₆Alkyl or hydroxyethyl;

R₂is C₁-C₁₀An alkyl group;

ar is C₅-C₁₀Arylene or heteroarylene; and

m and n are each independently 1 to 6;

the method comprises the following steps:

a) reacting compound (2)

Wherein p is 0 to 5;

and has the structure R₁The alcohol of-OH is reacted under suitable esterification conditions to provide compound (3)

(b) Reacting the compound (3) with the compound (5)

Wherein Z is a protecting group,

coupling under suitable conditions to provide Compound (6)

(c) Subjecting compound (6) to sufficient reducing conditions to provide compound (7)

(d) Reacting the compound (7) with the compound (8)

Coupling under suitable conditions to provide Compound (9)

(e) Subjecting the compound (9) to acidifying conditions,

thereby providing a compound of general structure (1).

2. The method of claim 1, wherein Ar is phenylene or naphthylene.

3. The method of claim 1, wherein Ar is phenylene.

4. The method of claim 1, wherein R₁Is C₃An alkyl group.

5. The method of claim 1, wherein R₁Is isopropyl.

6. The method of claim 1, wherein R₂Is straight chain C₅An alkyl group.

7. The method of claim 1, wherein m and n are 1.

8. The method of claim 1, wherein the protecting group is R₃R₄R₅SiCl, wherein R₃、R₄And R₅Each independently is C₁-C₄Straight or branched chain alkyl.

9. The process of claim 1, wherein coupling step (b) is carried out in the presence of a metal halide catalyst.

10. The method of claim 9, wherein the catalyst is a copper halide.

11. The method of claim 9, wherein the catalyst is CuI.

12. The method of claim 1, wherein the compound (I) has the structure:

Technical Field

The present invention relates generally to the synthesis of substituted gamma lactams that are useful as pharmaceutical compounds, for example, as pharmaceutical compounds useful for treating glaucoma and/or reducing elevated intraocular pressure.

Summary of The Invention

In the embodiments of the invention, the compounds are useful for treating ocular disorders such as, for example, glaucoma, lowering elevated intraocular pressure, and the like.

In embodiments of the invention, a process for preparing a compound having the general structure (1) is provided

Wherein:

R₁is H, C₁-C₆Alkyl or hydroxyethyl;

R₂is C₁-C₁₀An alkyl group;

ar is C₅-C₁₀Arylene or heteroarylene; and

m and n are each independently 1 to 6.

These methods can be carried out, for example, by the following steps:

a) reacting compound (2)

Wherein p is 0 to 5;

and has the structure R₁The alcohol of-OH is reacted under suitable esterification conditions to provide compound (3)

(b) Reacting the compound (3) with the compound (5)

Wherein Z is a protecting group,

coupling under suitable conditions to provide Compound (6)

(c) Subjecting compound (6) to sufficient reducing conditions to provide compound (7)

(d) Reacting the compound (7) with the compound (8)

Coupling under suitable conditions to provide Compound (9)

(e) Subjecting the compound (9) to acidifying conditions,

thereby providing a compound of general structure (1).

Detailed Description

It is to be understood that both the foregoing -general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed unless specifically stated otherwise, as used herein, the singular, including the plural, unless otherwise specified.

Unless specific definitions are provided, laboratory procedures and techniques are known in the art regarding nomenclature used in synthetic organic and inorganic chemistry and analytical chemistry described herein. Standard chemical symbols are used interchangeably with the full name represented by these symbols. Thus, for example, the terms "hydrogen" and "H" are understood to have the same meaning. Chemical synthesis, chemical analysis, and formulation can be performed using standard techniques.

As used herein, "alkyl" refers to a straight or branched chain hydrocarbon group having from 1 to about 100 carbon atoms. Whenever a numerical range (e.g. "1 to 100" or "C)₁-C₁₀₀") when appearing herein, it refers to every integers within the given range, e.g.," C₁-C₁₀₀Alkyl "means that the alkyl group may contain the only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. to 100 carbon atoms and includes 100 carbon atoms, but the term" alkyl "also includes instances where a numerical range of carbon atoms is not specified. "substituted alkyl" refers to an alkyl moiety bearing substituents including: alkyl, alkenyl, alkynylHydroxy, oxo, alkoxy, mercapto, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, haloalkyl, cyano, nitro, nitrone, amino, lower alkylamino, lower alkyldiamino, amido, azido, -C (O) H, -C (O) R₇、-CH₂OR₇、-C(O)-、-C(O)-、-S-、-S(O)₂-OC (O) -O-, wherein R₇Is H or lower alkyl; acyl, oxyacyl, carboxyl, carbamate, sulfonyl, sulfonamide, thioacyl, and the like. "lower alkyl" as used herein refers to an alkyl moiety having from 1 to about 6 carbon atoms.

"alkenyl" as used herein refers to a straight or branched chain hydrocarbon group having at least carbon-carbon double bonds and having in the range of from about 2 to about 100 carbon atoms, and "substituted alkenyl" refers to an alkenyl group which may be further substituted with or more substituents as described above.

"alkynyl" as used herein refers to a straight or branched chain hydrocarbon group having at least carbon-carbon triple bonds and having in the range of from about 2 to about 100 carbon atoms, and "substituted alkynyl" refers to an alkynyl group further bearing or more substituents as described above.

As used herein, "cycloalkyl" refers to a cyclic (i.e., ring-containing) alkyl moiety typically containing in the range of about 3 to about 8 carbon atoms, and "substituted cycloalkyl" refers to cycloalkyl further bearing or more substituents as set forth above.

As used herein, "aryl" refers to an aromatic group having in the range of 5 to 14 carbon atoms and "substituted aryl" refers to an aryl group further bearing or more substituents as described above.

"heteroaryl" as used herein refers to an aromatic moiety containing or more heteroatoms (e.g., N, O, S, etc.) as the part of the ring structure and having in the ring structure in total atoms (i.e., carbon atoms and heteroatoms) in the range of 5 to 14 "substituted heterocycle" refers to a heterocyclic group further bearing or more substituents as set forth above to .

As used herein, "heterocycle" refers to a non-aromatic cyclic (i.e., ring-containing) group containing or more heteroatoms (e.g., N, O, S, etc.) as the part of the ring structure and having in the range of 3 to 14 carbon atoms, and "substituted heterocycle" refers to a heterocyclic group further bearing or more substituents as set forth above to .

As used herein, "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine. "fluoro, chloro, bromo or iodo" may also be referred to as "fluoro, chloro, bromo or iodo".

As used herein, "arylene" refers to an aromatic ring or ring system that connects two other parts of a molecule, i.e., the two parts are bonded to the ring at two different ring positions. "Heteroarylene" refers to a heteroaromatic ring or heteroaromatic ring system that connects two other parts of a molecule. The arylene or heteroarylene group may be substituted or unsubstituted. An unsubstituted arylene or heteroarylene group has no substituent other than the two moieties to which it is attached in the molecule. The substituted arylene or heteroarylene group has a substituent in addition to two moieties attached thereto in a molecule.

The present invention provides processes that can be used to prepare pharmaceutically useful substituted gamma lactams. These methods can be carried out, for example, by the following steps:

a) reacting compound (2)

Wherein p is 0 to 5;

and has the structure R₁The alcohol of-OH is reacted under suitable esterification conditions to provide compound (3)

(b) Reacting the compound (3) with the compound (5)

Wherein Z is a protecting group,

coupling under suitable conditions to provide Compound (6)

(c) Subjecting compound (6) to sufficient reducing conditions to provide compound (7)

(d) Reacting the compound (7) with the compound (8)

Coupling under suitable conditions to provide Compound (9)

(e) Subjecting the compound (9) to acidifying conditions,

thereby providing a compound of general structure (1).

In embodiments of the invention, Ar is phenylene or naphthylene.

In some embodiments, R₁Is C₃An alkyl group. In certain embodiments, R₁Is isopropyl.

In some embodiments, R₂Is straight chain C₅An alkyl group.

In other embodiments of the invention, m and n are 1.

in the inventionIn some embodiments, the protecting group "Z" is R₃R₄R₅SiCl, wherein R₃、R₄And R₅Each independently is C₁-C₄Straight or branched chain alkyl.

In embodiments of the invention, a metal halide catalyst that performs the coupling step (c) in the presence of a metal halide catalyst is contemplated for use in the practice of the invention and is well known to those skilled in the art in embodiments the metal halide catalyst is a copper halide in certain embodiments the metal halide catalyst is CuI.

Exemplary compounds prepared by the synthetic methods of the present invention have the structure shown below:

the methods described in schemes 1 to 3 below may vary depending on the scale of the reaction or the geometry of the apparatus. The reaction time, temperature and amount of reagents shown can be varied within reasonable limits as empirically indicated to improve process efficiency without adversely affecting product characteristics. All reactions were carried out under an inert atmosphere in a suitable reactor equipped with appropriate stirring and temperature control.

An exemplary synthetic overview is set forth in scheme 1 below, wherein intermediate a is prepared.

Scheme 1

An exemplary synthetic route for intermediate B is outlined in scheme 2 below.

Scheme 2

Scheme 3 below outlines the final synthetic part leading to an exemplary compound of the present invention, compound a.

Scheme 3

The following examples are intended only to illustrate the invention and should in no way be considered as limiting the invention.

Examples

Synthesis of (R) -5-oxo-pyrrolidine-2-carboxylic acid ethyl ester

The reaction solution was concentrated under reduced pressure after hours of stirring at ambient temperature to give a yellow oil after slowly adding trimethylchlorosilane to a flask containing absolute ethanol and D-pyroglutamic acid at ambient temperature (about 23 ℃) while maintaining the reaction temperature no higher than 30 ℃. the product was dissolved in toluene and concentrated under reduced pressure to give a yellow oil the crude product was dissolved in dichloromethane and stirred while slowly adding saturated aqueous sodium bicarbonate until pH 7-8 was reached, the organic layer was separated and the aqueous layer was extracted with dichloromethane in steps, the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product (R) -5-oxo-pyrrolidine-2-carboxylic acid ethyl ester as a yellow oil.

Synthesis of [ (S) -1- (4-bromo-phenyl) -hexyloxy ] -tert-butyl-dimethyl-silane

Containing CH containing (S) -1- (4-bromo-phenyl) -hex-1-ol to the bottom at ambient temperature (about 23 ℃ C.)₂Cl₂The reaction mixture was stirred times at ambient temperature until all starting material was consumed, after which time the reaction mixture was quenched with a mixture of MeOH and water.

Synthesis of ethyl (R) -1- (4- ((S) -1- (tert-butyldisilyloxy) hexyl) phenyl) -5-oxopyrrolidine-2-carboxylate

To a flask containing acetonitrile are added [ (S) -1- (4-bromo-phenyl) -hexyloxy ] -tert-butyl-dimethyl-silane and potassium carbonate the solution mixture is heated to reflux for periods of time after which the solution mixture is cooled to ambient temperature (about 23 ℃) before adding a solution of (R) -5-oxo-pyrrolidine-2-carboxylic acid ethyl ester in acetonitrile, CuI and N, N' -dimethylethylenediamine the reaction mixture is heated to reflux until the ethyl ester is consumed, the reaction mixture is cooled to ambient temperature, filtered through a bed of celite and rinsed forward with acetonitrile, the filtrate is washed twice with aqueous ammonium acetate and dried over sodium sulfate, the mixture is passed through a bed of silica, washed with MTBE, and concentrated under reduced pressure to give the product as a light yellow oil.

Synthesis of (R) -1- {4- [ (S) -1- (tert-butyl-dimethyl-silanyloxy) -hexyl ] -phenyl } -5-hydroxymethyl-pyrrolidin-2-one

To a flask containing ethanol and (R) -1- {4- [ (S) -1- (tert-butyl-dimethyl-silanyloxy) -hexyl ] -phenyl } -5-oxo-pyrrolidine-2-carboxylic acid ethyl ester was added aqueous dipotassium hydrogen phosphate followed by aqueous sodium borohydride solution while maintaining the reaction at ambient temperature (about 23 ℃). The mixture was stirred at ambient temperature until all ethyl esters were consumed, then quenched with water and then extracted with MTBE. The combined organic extracts were washed with brine and concentrated under reduced pressure to give the crude product as an off-white solid. The crude product was recrystallized using heptane to give pure product.

Synthesis of isopropyl 5- (bromomethyl) thiophene-2-carboxylate

Step 5 comprises converting the commercially available starting material 5-methylthiophene-2-carboxylic acid to its isopropyl 5-methylthiophene-2-carboxylate to generate the acid chloride in situ, and then reacting the acid chloride with IPA. Step 6 the pure product was obtained by free radical reaction with NBS (N-bromosuccinimide) and peroxide in perchloroethylene to convert 5-methylthiophene-2-carboxylate to isopropyl 5- (bromomethyl) thiophene-2-carboxylate, followed by recrystallization from heptane.

Synthesis of 5- { (R) -1- [4- ((S) -1-hydroxy-hexyl) -phenyl ] -5-oxo-pyrrolidin-2-ylmethoxymethyl } -thiophene-2-carboxylic acid isopropyl ester (crude)

Containment of (R) -1- {4- [ (S) -1- (tert-butyl-dimethyl-silanyloxy) -hexyl at ambient temperature (about 23 ℃ C.) was performed]-phenyl } -5-hydroxymethyl-pyrrolidin-2-one and 5- (bromomethyl) thiophene-2-carboxylic acid isopropyl ester in CH₂Cl₂To a flask of the mixture in (1) was slowly added 50% aqueous NaOH followed by tbab stirring the reaction mixture at ambient temperature for time periods until (R) -1- {4- [ (S) -1- (tert-butyl-dimethyl-silanyloxy) -hexyl]Phenyl } -5-hydroxymethyl-pyrrolidin-2-one is depleted, then carbon dioxide is bubbled into the stirred biphasic reaction mixture until the pH of the aqueous layer reaches no greater than 7, stirring is stopped and the reaction mixture is allowed to separate into an aqueous layer and an organic layer, the aqueous layer is washed several times with DCM, the DCM wash is combined with the organic layer and concentrated in vacuo until drying to give the crude product, then the crude product is dissolved in isopropanol and stirred at ambient temperature (about 23 ℃) until the solution becomes homogeneous, aqueous acid is added to the reaction solution and stirred at ambient temperature (about 23 ℃) for hours until HPLC analysis indicates no more starting material remainsThe crude product was obtained as a yellow to amber oil.

Purification of 5- { (R) -1- [4- ((S) -1-hydroxy-hexyl) -phenyl ] -5-oxo-pyrrolidin-2-ylmethoxymethyl } -thiophene-2-carboxylic acid isopropyl ester

Crude 5- { (R) -1- [4- ((S) -1-hydroxy-hexyl) -phenyl ] -5-oxo-pyrrolidin-2-ylmethoxymethyl } -thiophene-2-carboxylic acid isopropyl ester was dissolved in MTBE, then applied to a silica gel column and used for gradient elution of MTBE in n-heptane. The fractions containing the crude product (> 98% (a/a) by HPLC) were combined and concentrated under reduced pressure to give a yellow oil. The product was then dissolved in IPA, passed through a capsule fine filter, and then concentrated under reduced pressure at not higher than 40 ℃ to give the pure product as a yellow to amber oil.

Table 1: chemical Shift assignment of Compound A^1，2

1 DMSO-d₆At 26 ℃. Proton reference DMSO-d₆. Carbon reference DMSO-d₆。

2 standard abbreviations: s is singlet; d is bimodal; t is a triplet; q is quartet; qui ═ quintuple; m is multiplet; br is broad peak; overlap (too much overlap to perform integration and/or multiplicity determination)

Although the invention has been described with respect to these specific embodiments, it will be appreciated that other modifications and variations are possible without departing from the spirit of the invention.