HK1036270A - Process for alkylating hindered sulfonamides useful in the production of matrix metal-loproteinase inhibitors - Google Patents

Process for alkylating hindered sulfonamides useful in the production of matrix metal-loproteinase inhibitors Download PDF

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HK1036270A
HK1036270A HK01106638.4A HK01106638A HK1036270A HK 1036270 A HK1036270 A HK 1036270A HK 01106638 A HK01106638 A HK 01106638A HK 1036270 A HK1036270 A HK 1036270A
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heteroaryl
aryl
alkyl
radical
group
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HK01106638.4A
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B‧M‧安德森
P‧D‧翰门
J‧M‧霍金斯
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辉瑞产品公司
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Description

Alkylation of hindered sulfonamides for the preparation of matrix metalloproteinase inhibitors
In accordance with 35 USC, section 119(e), this application claims priority from U.S. provisional application 60/081310 filed on 10.4.1998, the entire text of which is incorporated herein by reference. U.S. patent application entitled "method for alkylating hindered sulfonamides" filed on 9.4.1999, also incorporated herein by reference in its entirety, is identified as EE 645346913 US, a postal express.
Background
The present invention relates to a process for alkylating hindered sulfonamides via the michael addition of a propiolate and intermediates prepared in said process. The reaction product can be converted into a matrix metalloproteinase inhibitor.
Matrix metalloproteinase inhibitors (MMPs) are known to be useful in the treatment of conditions selected from the group consisting of: arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergy, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, artificial implant joint relaxation, atherosclerosis (including atherosclerotic platelet rupture), aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neurodegenerative disorders (acute and chronic), autoimmune disorders, Huntington's chorea, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, Psychotropic or cognition-enhanced, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor morbidity, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis, septic shock, and other diseases characterized by inhibition of metalloproteinase or ADAM (including TNF- α) expression. In addition, the products that can be prepared from the compounds and methods of the present invention can also be used in combination therapy for arthritis with: standard non-steroidal anti-inflammatory drugs (hereinafter NSAIDs), COX-2 inhibitors and analgesics; in combination therapy with: cytotoxic drugs such as doxorubicin, daunorubicin, cisplatin, etoposide, taxol, taxotere, and alkaloids such as vincristine.
Alkylsulfonamides which can be prepared by the process of the invention are described in the literature. PCT publications W096/27583 and WO98/07697, published respectively at 3/7 th 1996 and 2/26 th 1998, relate to arylsulfonyl hydroxamic acids. The above references relate to processes for preparing sulfonamides using processes other than those described in the present invention. All of the above references are incorporated herein by reference in their entirety.
Summary of The Invention
The present invention relates to compounds of the formula
Wherein R is1Is (C)1-C6) Alkyl or optionally substituted benzyl;
R2and R3Independently is (C)1-C6) Alkyl, or R2And R3Together form a three-to seven-membered cycloalkyl, pyran-4-yl ring or bicyclic ring of the formula
Wherein the asterisks indicate R2And R3A common carbon atom;
q is (C)1-C6) Alkyl, (C)6-C10) Aryl group, (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkyl, (C)6-C10) Aryloxy radical (C)1-C6) Alkyl, (C)6-C10) Aryloxy radical (C)6-C10) Aryl group, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)6-C10) Aryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryloxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryloxy (C)6-C10) Aryl group, (C)2-C9) Heteroaryloxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)6-C10) Aryl or (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)2-C9) A heteroaryl group;
wherein said (C)6-C10) Aryl group, (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkyl, (C)6-C10) Aryloxy radical (C)1-C6) Alkyl, (C)6-C10) Aryloxy radical (C)6-C10) Aryl group, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)6-C10) Aromatic hydrocarbonBase, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryloxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryloxy (C)6-C10) Aryl group, (C)2-C9) Heteroaryloxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)6-C10) Aryl or (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)2-C9) Each (C) of heteroaryl6-C10) Aryl or (C)2-C9) The heteroaryl moiety is optionally substituted on any additional ring carbon atom with one or more substituents independently selected from fluorine, chlorine, bromine, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, perfluoro (C)1-C3) Alkyl, perfluoro (C)1-C3) Alkoxy and (C)6-C10) An aryloxy group;
y is hydrogen, (C)1-C6) Alkyl groups or suitable protecting groups.
Preferred compounds of formula IV are those in which R is2And R3Together form a cyclobutyl, cyclopentyl, pyran-4-yl ring or a bicyclic ring of formula
Wherein the asterisks indicate R2And R3A common carbon atom;
wherein Q is 4- (4-fluorophenoxy) phenyl.
The invention also relates to a process for the preparation of a compound of the formula
Wherein R is1、R2、R3Q and Y are as defined above;
the process comprises reacting a compound of the formula
Wherein R is1Is an optionally substituted benzyl group; r2、R3And Q is as defined above;
with a compound of the formula
Wherein Y is (C)1-C6) An alkyl group;
the reaction is carried out in the presence of a base such as tetrabutylammonium fluoride, potassium carbonate, tertiary amine and cesium carbonate, preferably tetrabutylammonium fluoride, and a polar solvent such as tetrahydrofuran, acetonitrile, tert-butanol, t-pentanol and N, N-dimethylformamide, preferably tetrahydrofuran.
The invention also relates to a process comprising reducing the compound of the formula
Wherein R is1、R2、R3Y and Q are as defined above;
the reducing agent is, for example, a palladium catalyst and a hydrogen source, preferably hydrogen on palladium-carbon, and the reaction is carried out in a solvent, such as an alcohol or tetrahydrofuran, preferably ethanol, to form the compound of the formula
Wherein R is4Is hydrogen;
R2、R3y and Q are as defined above.
The invention also relates to a process further comprising reacting said compound of formula III (wherein R is4Is hydrogen) with an amine, such as dicyclohexylamine, to form an amine salt of the compound of formula iii, such as dicyclohexylammonium salt.
The term "protecting group" as a substituent represented by Y is as described in Greene and Wuts protective group in organic Synthesis (John Wiley & Sons, Inc., Wiley Interscience Second Edition, 1991).
The term "alkyl" as used herein, unless otherwise specified, includes saturated monovalent hydrocarbon radicals having straight, branched, or cyclic moieties or combinations thereof.
The term "alkoxy" as used herein includes O-alkyl, wherein "alkyl" is as defined above.
The term "aryl" as used herein, unless otherwise specified, includes organic radicals derived from aromatic hydrocarbons by removal of one hydrogen, such as phenyl or naphthyl.
The term "heteroaryl" as used herein, unless otherwise specified, includes organic radicals derived from aromatic heterocyclic compounds by removal of one hydrogen, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl or benzoxazolyl. Preferred heteroaryl groups include pyridyl, furyl, thienyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyrazolyl, isoxazolyl, thiazolyl, or oxazolyl. Most preferred heteroaryl groups include pyridyl, furyl or thienyl.
The term "acyl" as used herein, unless otherwise specified, includes radicals of the general formula R- (C = O) -, wherein R is alkyl, alkoxy, aryl, aralkyl or aralkoxy, and the terms "alkyl" or "aryl" are as defined above.
The term "acyloxy", as used herein, includes O-acyl groups, wherein "acyl" is as defined above.
Wave curve in formula IV (i.e.) This means that the carboxyl group may exist in either a cis or trans configuration.
The compounds of the formulae I to V may have chiral centers and thus exist in different diastereomeric or enantiomeric forms. The invention also relates to all optical isomers, tautomers and stereoisomers of the compounds of formula I-V and mixtures thereof.
Preferably, the compounds of formula I' are present as the exo-isomers of the formula
Improved synthetic route with improved yield
The present invention also relates to an improved process for the preparation of compounds of structure (formula) I of scheme I (see the detailed description of the invention below),
and to novel intermediates useful in this regard. The compounds of structure I have important pharmacological activities. Accordingly, there is provided a preferred intermediate compound according to structure IV above,
wherein R is1Is [ (A)1)CH2]c[(A2)CH2]b[(A3)CH2]aC-, wherein a, b and C are each 1; each A is1、A2And A3Independently selected from the group consisting of H, (C)1-C5) Alkyl and phenyl or substituted phenyl. In the preferred embodiment，R1Is a tert-butyl group; thus A1、A2And A3Each is hydrogen.
As described in detail below, providing this intermediate facilitates the synthesis of the pharmaceutical compounds of the present invention in high yields. Briefly, in a Michael addition reaction (see below, for use in the preliminary synthetic steps herein), with other R's as disclosed herein1Definitions, e.g. including benzyl, if R is1Is defined according to this particular case of the invention1Is [ (A)1)CH2]c[(A2)CH2]b[(A3)CH2]aC-, wherein a, b and C are each 1; each A is1、A2And A3Independently selected from the group consisting of H, (C)1-C5) Alkyl and phenyl or substituted phenyl), then reacting a compound of the formula
With a compound of the formula,
it has been determined that substantially and surprisingly advantageous results can be obtained.
The present invention therefore provides a process for the preparation of a compound of the formula, for example
Wherein R is1Is [ (A)1)CH2]c[(A2)CH2]b[(A3)CH2]aC-, wherein a, b and C are each 1; each A is1、A2And A3Independently selected from the group consisting of H, (C)1-C5) Alkyl groups and phenyl or substituted phenyl groups, and methods of further using them are provided.
The further method comprises reducing said compound IV with a reducing agent
Wherein R is1Is [ (A)1)CH2]c[(A2)CH2]b[(A3)CH2]aC-, wherein a, b and C are each 1; each A is1、A2And A3Independently selected from the group consisting of H, (C)1-C5) Alkyl and phenyl or substituted phenyl, R2、R3Y and Q are as defined above,
to form a compound of the formula
In another aspect of the present invention, the process further comprises hydrolyzing the above compound under acidic conditions, wherein R is1、R2、R3Y and Q are as defined above to form a compound of the formula
Wherein R is2、R3Y and Q are as defined above.
In another embodiment of the invention, a compound of the formula is first hydrolyzed under acidic conditions,
wherein R is1、R2、R3Y and Q are as defined above to form a compound of the formula
Wherein R is2、R3Y and Q remain as defined above; then, a second reaction step of treating compound (a) with a reducing agent to produce a compound of the formula
Wherein R is2、R3Y and Q are as defined above.
Detailed Description
The following reaction scheme illustrates the preparation of the compounds of the present invention. Unless otherwise specified, n, R in the reaction schemes and the discussion that follows1、R2、R3Q and Z are as defined above.
Scheme 1
Scheme 1 continues
Scheme 1 relates to the preparation of matrix metalloproteinase inhibitory compounds of formula I.
Referring to scheme 1, compounds of formula I are prepared from compounds of formula II by reaction with in situ generated silylated hydroxylamine followed by treatment with an acid. Specifically, the in situ generated silylated hydroxylamine compounds are prepared from hydroxylamine hydrochloride or hydroxylamine sulfate, preferably hydroxylamine hydrochloride, by reacting ((C) in the presence of a base1-C4) Alkyl) 3 silyl halide to form O-trimethylsilylhydroxylamine, N, O-bistrimethylsilylhydroxylamine, or combinations thereof. Suitable bases include pyridine, 2, 6-lutidine or diisopropylethylamine, preferably pyridine. The reaction is carried out at a temperature of about 0 ℃ to about 22 ℃ (i.e., room temperature) for about 1 to about 12 hours, preferably about 1 hour. Suitable acids include hydrochloric acid or sulfuric acid, preferably hydrochloric acid.
The compound of formula II is preferably not isolated, from which R4The compound of formula III is hydrogen, prepared by reaction with oxalyl chloride or thionyl chloride, preferably oxalyl chloride, and a catalyst, preferably about 2% N, N-dimethylformamide, in an inert solvent such as dichloromethane or toluene. The reaction is carried out at a temperature of about 0 ℃ to about 22 ℃ (i.e., room temperature) for about 1 to about 12 hours, preferably about 1 hour.
Wherein R is4Compounds of formula III which are hydrogen may be prepared from those in which R is1Is optionally substituted benzylThe compounds of formula IV are prepared by reduction in a polar solvent. Suitable reducing agents include a source of hydrogen and a palladium catalyst, for example hydrogen on palladium, hydrogen on palladium-carbon or hydrogen on palladium hydroxide-carbon, preferably hydrogen on palladium-carbon. Suitable solvents include tetrahydrofuran, methanol, ethanol and isopropanol and mixtures thereof, preferably ethanol. The above reaction is carried out at a temperature of about 22 deg.c (i.e., room temperature) for about 1 to about 7 days, preferably about 2 days.
Wherein R is5Compounds of the formula III which are not hydrogen, e.g. are protonated amines (such as protonated primary, secondary or tertiary amines), alkali metals or alkaline earth metals, may be prepared from those compounds of the formula III in which R is5The compounds of formula III are hydrogen prepared by treatment with an aqueous or alcoholic solution containing an acceptable cation, such as sodium, potassium, dicyclohexylamine, calcium and magnesium, preferably dicyclohexylamine, and then evaporating the resulting solution to dryness, preferably under reduced pressure, or filtering the precipitate, preferably a dicyclohexylamine salt precipitate.
Wherein R is1Is (C)1-C6) The compounds of formula IV of alkyl or optionally substituted benzyl may be prepared from those wherein R1Compounds of formula V which are optionally substituted benzyl are prepared by Michael addition with a propiolate in a polar solvent in the presence of a base. Suitable propiolates are H-C.ident.C-CO2Y, wherein Y is (C)1-C6) An alkyl group. Formula H-C ≡ C-CO2The Y compounds are commercially available or may be prepared by methods well known to those of ordinary skill in the art. Suitable bases include tetrabutylammonium fluoride, potassium carbonate, tertiary amines and cesium carbonate, with tetrabutylammonium fluoride being preferred. Suitable solvents include tetrahydrofuran, acetonitrile, t-butanol, t-pentanol and N, N-dimethylformamide, preferably tetrahydrofuran. The above reaction is carried out at a temperature of from about-10 ℃ to about 60 ℃, preferably between 0 ℃ and about 22 ℃ (i.e., room temperature). The resulting compound of formula IV is a mixture of geometric isomers (i.e., cis and trans isomers) with respect to the olefinic double bond, and separation of the isomers is not necessary.
Wherein Y is (C)1-C6) Alkyl compounds of formula I may be saponified with a base such as sodium hydroxide to the free acid (i.e. Y is hydrogen) in a protic solvent such as ethanol, methanol or water, or in a mixed solvent such as water and ethanol, water and toluene or water and THF. Preferred solvent systems are water and toluene. The reaction is carried out for 30 minutes to 24 hours, preferably about 2 hours.
Wherein R is1Compounds of formula v which are optionally substituted benzyl groups may be prepared according to methods known in the art. The alkylsulfonamides and starting materials of formula V which can be prepared by the process of the invention are also described in the literature. PCT publications WO 96/27583 and WO98/07697, published respectively at 3.7.1996 and 2.26.1998, relate to arylsulfonyl hydroxamic acids. The entire disclosures of the above-referenced publications are incorporated herein by reference.
Wherein R is2And R3Compounds of formula V which are tetrahydropyran-4-yl or bicyclic of formula may be prepared in analogy to examples 2 and 3
Wherein the asterisks indicate R2And R3A common carbon atom.
The basic compounds of formula I are capable of forming a variety of different salts with different inorganic and organic acids. These salts must be pharmaceutically acceptable for animal administration, although in practice it is generally necessary to isolate the pharmaceutically unacceptable salt of the compound of formula I from the reaction mixture and then simply convert the latter to the free base compound by treatment with a basic agent followed by conversion of the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with substantially equal amounts of the selected inorganic or organic acid, in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. The desired solid salt is obtained by careful evaporation of the solvent.
The acids used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, and pamoate (i.e., 1' -methylene-bis (2-hydroxy-3-naphthoate)).
The acidic compounds of formula i are capable of forming base salts with different pharmaceutically acceptable cations. Examples of salts include alkali metal or alkaline earth metal salts, particularly sodium and potassium salts. These salts are prepared by conventional techniques. The chemical bases used as reagents to prepare the pharmaceutically acceptable base salts of the present invention are those which form non-toxic base salts with the acidic compounds of formula I described herein. Such non-toxic base salts include those derived from pharmaceutically acceptable cations such as sodium, potassium, calcium, magnesium, and the like. These salts can be readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may be prepared by mixing together a lower alcohol solution of the acidic compound and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as described above. In both cases it is preferred to use stoichiometric amounts of reagents to ensure complete reaction and maximum yield.
The ability of a compound of formula i or a pharmaceutically acceptable salt thereof (hereinafter also referred to as an active compound) to inhibit matrix metalloproteinase or ADAM (e.g., inhibit the production of Tumor Necrosis Factor (TNF)) can be determined based on in vitro assays well known to those of ordinary skill in the art, thereby demonstrating its efficacy in treating diseases characterized by matrix metalloproteinase or ADAM (e.g., the production of tumor necrosis factor). An example of an assay that is believed to demonstrate the efficacy of the final product prepared by the method of the present invention is the following inhibition assay for human collagenase.
Preferred examples of the invention
The present invention also relates to an improved process for the preparation of compounds of structure (formula) I of scheme I (see the detailed description of the invention below),
and to novel intermediates useful in this regard. The compounds of structure I have important pharmacological activities. There is thus provided a preferred intermediate compound of structure IV as hereinbefore described,
wherein R is1Is [ (A)1)CH2]c[(A2)CH2]b[(A3)CH2]aC-, wherein a, b and C are each 1; each A is1、A2And A3Independently selected from the group consisting of H, (C)1-C5) Alkyl and phenyl or substituted phenyl. In a preferred embodiment, R1Is a tert-butyl group; thus A1、A2And A3Each is hydrogen.
The provision of such intermediate compounds facilitates the synthesis of the pharmaceutical compounds of the present invention in high yields. In the Michael addition reaction (see below, for use in the preliminary synthesis step herein), if R1Is defined according to this particular example of the invention (that is, R1Is [ (A)1)CH2]c[(A2)CH2]b[(A3)CH2]aC-, wherein a, b and C are each 1; each A is1、A2And A3Independently selected from the group consisting of H, (C)1-C5) Alkyl and phenyl or substituted phenyl), then reacting a compound of the formula
With a compound of the formula,
it has been determined that substantially and surprisingly advantageous results can be obtained. With other R as disclosed herein1This can be seen in comparison to, for example, benzyl or optionally substituted benzyl. Thus, it is preferred to use, for example, tert-butyl as R1Nevertheless, benzyl groups, for example, are very useful.
In accordance with the practice of the present invention, benzyl and substituted benzyl are as R1Is very useful. For example, as for the following structures
The reaction conditions (see above) can be chosen such that not only the carbon-carbon double bond is reduced, but also the benzyl group is cleaved from the carboxyl group in a one-step process. This seems to be very advantageous, however R1The presence of the upper or substituted benzyl group allows side reactions to occur which may reduce the overall efficiency of the michael addition reaction to be carried out. While the practice of the present invention is not bound by any theory, it may be important to determine the efficiency of the overall synthesis scheme to improve the efficiency of the michael reaction, even at the expense of the simplicity of the subsequent steps. Thus, the present example provides an alternative to other useful processes of the present invention.
Also not to be limited by theory, in the Michael addition, R1E.g. tert-butyl to other R1For example, benzyl groups are more likely to interfere with side reactions (e.g., by steric hindrance). This effect may be more important to the success of the overall reaction with respect to coupling efficiency. Thus, the practice of the present invention encompasses an alternative efficient method of producing intermediate compounds necessary for efficient production of active pharmaceutical agents.
The invention therefore provides a process for the preparation of, for example, a compound of the formula,
wherein R is1Is [ (A)1)CH2]c[(A2)CH2]b[(A3)CH2]aC-, wherein a, b and C are each 1; each A is1、A2And A3Independently selected from the group consisting of H, (C)1-C5) Alkyl groups and phenyl or substituted phenyl groups, and methods of further using them are provided.
With respect to R1It is contemplated that other groups having a t-butyl effect, or other groups found based on the general teachings herein, may be used. Thus, the skilled artisan will recognize that any group that is more capable of reducing the rate of side reactions during the Michael addition process relative to benzyl is generally used as R1Are within the practice of the invention.
The further method comprises reducing said compound IV with a reducing agent
Wherein R is1Is [ (A)1)CH2]c[(A2)CH2]b[(A3)CH2]aC-, wherein a, b and C are each 1; each A is1、A2And A3Independently selected from the group consisting of H, (C)1-C5) Alkyl and phenyl or substituted phenyl, R2、R3Y and Q are as defined above,
to form a compound of the formula
In another aspect of the present invention, the process further comprises hydrolyzing the above compound under acidic conditions, wherein R is1、R2、R3Y and Q are as defined above to form a compound of the formula
Wherein R is2、R3Y and Q are as defined above.
In the practice of the invention with respect to YBy selection, it is noted that preference is given to hydrogen or (C)1-C6) Alkyl is used as Y in the compounds of the invention. With regard to the above process (considering the above conversion of structure (i) directly to structure (ii)), Y is very preferably (C)1-C6) An alkyl group. (C)1-C6) An especially important property of an alkyl group is that, although it readily hydrolyzes under basic conditions, it is suitable to counteract hydrolysis under acidic conditions, whereas the present invention uses acidic hydrolysis in practice. Thus, for example, when R1In the case of t-butyl, the preferred hydrolysis may be carried out under moderately acidic conditions (see, e.g., example 4) to cleave the t-butyl while leaving the Y moiety in place as a functional group. Due to Y, i.e. (C)1-C6) Alkyl groups are more resistant to the formation of acid chlorides and subsequent introduction of hydroxamic acids than newly exposed carboxyl groups, and the final chemistry of the present invention may involve the appropriate desired carbonyl group. In the practice of the present invention, the compound is1-C6) In addition to alkyl groups, other groups may be used which achieve the same functional result.
In another embodiment of the invention, a compound of the formula is first hydrolyzed under acidic conditions,
wherein R is1、R2、R3Y and Q are as defined above to form a compound of the formula
Wherein R is2、R3Y and Q remain as defined above; then, a second reaction step of treating compound (a) with a reducing agent to produce a compound of the formula
Wherein R is2、R3Y and Q are as defined above.
With respect to the above reactions, hydrolysis under acidic conditions may involve the use of different acids. Among the mineral acids, mention may be made of HCl,HBr and H2SO4. Suitable carboxylic acids, such as formic acid and trifluoroacetic acid, may also be used. Other classes of useful acids include, but are not limited to, sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid.
The reduction conditions used according to this aspect of the invention are described below. The reducing agent is hydrogen on a catalyst selected from the group consisting of platinum oxide or raney nickel or on a supported catalyst selected from the group consisting of palladium-carbon or platinum-carbon, all of which are suitable catalytic conditions. Likewise, the determination of equally effective reagents and conditions will be recognized as within the knowledge of one of ordinary skill in the art.
Biological assay
Inhibition of human collagenase (MMP-1)
Human recombinant collagenase was activated with trypsin using the following ratios: 10 μ g trypsin per 100 μ g collagenase. Trypsin and collagenase were incubated at room temperature for 10 minutes, then a five-fold excess (50 μ g/10 μ g trypsin) of soybean trypsin inhibitor was added.
A 10mM stock solution of inhibitor was prepared in dimethyl sulfoxide and then diluted as follows:
10mM→120μM→12μM→1.2μM→0.12μM
then added to appropriate wells of a 96-well microfluorescent (microfluoror) plate at twenty-five microliters each in triplicate. After addition of enzyme and substrate, the final concentration of inhibitor will be diluted 1: 4. Positive controls (enzyme, no inhibitor) were placed in the D1-D6 wells and blanks (enzyme, no inhibitor) were placed in the D7-D12 wells.
Collagenase was diluted to 400ng/ml and then 25. mu.l was added to the appropriate wells of the microfluorescent plate. The final concentration of collagenase in the assay was 100 ng/ml.
Adding substrate (DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2) 5mM dimethyl sulfoxide stock solution was made and then diluted in assay bufferReleased to 20 mM. To each well of the microfluorescent plate was added 50. mu.l of substrate at a final concentration of 10. mu.M, and the assay was started.
Fluorescence readings (360nM excitation, 460nM emission) were recorded at time 0 and every 20 minutes. The measurement is carried out at room temperature, with a typical measurement time of 3 hours.
The fluorescence of the blank and the collagenase containing samples was then plotted against time (averaged over the three measurements). The time points (typically around 120 minutes) that gave a good signal (blank) and on the straight part of the curve were chosen and the IC was determined50The value is obtained. These values were subtracted from the 120 minute data using zero time as a blank for each compound at each concentration. Data were plotted as inhibitor concentration versus% control (fluorescence of inhibitor divided by fluorescence of collagenase alone x 100). The IC was determined as the concentration of inhibitor whose signal was equal to 50% of the control value50。
If the reported IC50Less than 0.03. mu.M, then the inhibitor is measured at a concentration of 0.3. mu.M, 0.03. mu.M and 0.003. mu.M.
The following examples illustrate the preparation of the compounds of the present invention. The melting point is uncorrected. NMR data are reported in parts per million (δ) and relate to the deuterium lock signal from the sample solvent (unless otherwise specified, the solvent is deuterated chloroform). Commercial reagents were used without further purification. THF means tetrahydrofuran. DMF refers to N, N-dimethylformamide. Chromatography refers to column chromatography using 32-63mm silica gel under nitrogen pressure (flash chromatography). The room temperature or ambient temperature means 20-25 ℃. All reactions without water were carried out under nitrogen for convenience and to improve yield. Concentration under reduced pressure refers to the use of a rotary evaporator.
Example 1
3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoyl-cyclopentyl) amino ] propanoic acid
A) Benzyl 1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclopentanecarboxylate
To a mixture of 12.41g (0.032mol) benzyl 1-aminocyclopentanecarboxylate, toluene-4-sulfonate (which can be prepared according to the literature, e.g. U.S. Pat. No. 4, 4745124) and 10.0g (0.035mol, 1.1 equivalents) 4- (4-fluorophenoxy) benzenesulfonyl chloride (prepared according to preparation 3) in 113ml toluene was added 11.0ml (0.079mol, 2.5 equivalents) triethylamine. The resulting mixture was stirred at ambient temperature overnight, washed with 2N hydrochloric acid (2X 100ml) and brine (100ml), dried over sodium sulphate and concentrated to 30 ml. 149ml of hexane were added dropwise over a period of three hours to give a solid precipitate, which was granulated at 0 ℃ for one hour and filtered to give 12.59g (85%) of benzyl 1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclopentanecarboxylate.
1H NMR(CDCl3)δ7.78-7.82(m,2H),7.30-7.39(m,5H),7.06-7.12(m,2H),6.99-7.04(m,2H),6.93-6.97(m,2H),5.15(s,1H),5.02(s,2H)，2.04-2.13(m,2H),1.92-1.98(m,2H),1.62-1.69(m,4H)。
A4.0 g sample was granulated overnight in a mixture of 4ml ethyl acetate and 40ml hexane to give 3.72g (93% recovery) benzyl 1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclopentanecarboxylate as a light brown solid, mp 97.0-97.5 ℃.
B) Benzyl 1- { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylate
25.0g (53.2mmol) of 1- [4- (4-fluorophenoxy) benzenesulfonylamino]Benzyl cyclopentanecarboxylate and 10.8ml (106mmol,2 equiv.) of ethyl propiolate in 200ml dry tetrahydrofuran are treated with 53.2ml (53.2mmol,1 equiv.) of tetrabutylammonium fluoride in tetrahydrofuran (1M) at 1 ℃ for 45 min. The resulting solution was slowly heated to ambient temperature and stirred overnight. Toluene was used instead of tetrahydrofuran under reduced pressure, and the toluene solution was washed with water and brine, diluted to 600ml with toluene, stirred with 90g of silica gel for three hours, filtered and concentrated to give 25.14g (83%) of 1- { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) benzenesulfonyl group]Amino } cyclopentanecarboxylic acid benzyl ester, an orange oil.1H NMR(CDCl3) Indicating a trans/cis ratio of 1.5: 1.
Trans δ 7.74-7.78(m,2H),7.72(d, J =14 Hz,1H),7.26-7.36(m,5H),6.96-7.12(m,4H),6.78-6.84 (m,2H),5.44(d, J =14 Hz,1H),5.11(s,2H),4.12(q, J =7.1Hz, 2H),2.08-2.43(m,4H),1.63-1.80(m,4H),1.24(t, J =7.1Hz,3H), cis δ 7.68-7.72(m,2H),7.26-7.36(m,5H),6.96-7.12(m,4H),6.86-6.91(m,2H),6.47(d, J = 8.1H, 1 = 90H), 1.93 (m,5H), 1.93-7.93 (m,4H), 3H), 4H) 1.17(t, J =7.2Hz, 3H).
C)1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid
A solution of 2.50g (4.4mmol) of benzyl 1- { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylate in 25ml of ethanol was treated with 2.5g of 10% palladium-on-carbon catalyst humidified with 50% water and shaken under 53psi of hydrogen for 21 hours. The catalyst was removed by filtration and washed with ethanol (4X 25 ml). The filtrate and washings were combined and concentrated in vacuo to give 1.74g (82%) of crude 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid as a viscous oil.
1H NMR(CDCl3)δ7.78-7.82(m,2H),6.94-7.09 (m,6H),4.09(q,J=7.2 Hz,2H),3.56-3.60(m,2H),2.75-2.79(m,2H),2.33-2.39(m,2H),1.93-2.03(m,2H),1.69-1.76(m,2H),1.56-1.63(m,2H),1.22(t,J=7.2 Hz,3H)。
D) Dicyclohexylammonium salt of 1- { (2-ethoxycarbonylethyl) 4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid
A solution of 3.l0g (6.5mmol) crude 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid in 30ml ethanol was treated with 1.28ml (6.5mmol, 1 eq) dicyclohexylamine at ambient temperature to give a solid in five minutes. The mixture was stirred at ambient temperature overnight and then at 0 ℃ for five hours. A white solid was isolated by filtration, washed with 10ml of cold ethanol and air-dried to give 2.89 g (67%) of the dicyclohexylammonium salt of 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid.
1H NMR(CDCl3)δ7.86-7.91(m,2H),6.99-7.09(m,4H),6.90-6.94(m,2H),5.3(br s,2H),4.07(q,J=7.1 Hz,2H),3.54-3.59(m,2H),2.88-2.95(m,4H),2.31-2.38(m,2H),1.95-2.22(m,6H),1.68-1.77(m,6H),1.53-1.60(m,4H),1.40-1.50(m,4H),1.21(t,J=7.1 Hz,3H),1.14-1.22(m, 6H). Mp164.5-165.9℃。
E)1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid
A solution of 3.0g (4.5mmol) of the dicyclohexylammonium salt of 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid in 30ml of dichloromethane was treated with 30ml of 2N hydrochloric acid at ambient temperature, resulting in immediate precipitation of the solid. The mixture was stirred at ambient temperature for three hours. The solid was filtered, the aqueous phase extracted with dichloromethane, and the combined organic phases washed with water, dried over sodium sulfate and concentrated in vacuo to give 2.2g (100%) of 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid as clear
1H NMR(DMSO-d6)δ12.68(bs,1H),7.76-7.80(m,2H),7,25-7.31(m,2H),7.16-7.21(m,2H),7.03-7.08(m,2H),4.01(q,J=7.1 Hz,2H),3.48-3.54(m,2H),2.64-2.70(m,2H),2.13-2.21(m,2H),1.90-1.98(m,2H), 1.52-1.59 (m,4H),1.14(t,J=7.1 Hz,3H)。
F)3- { (1-Chlorocarbonylcyclopentyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } propanoic acid Ethyl ester
A solution of 7.26g (15.1mmol) of 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid in 73ml of dichloromethane was treated with 1.4ml (17mmol,1.1 equiv.) of oxalyl chloride and 0.02ml (0.3mmol,0.02 equiv.) of dimethylformamide at ambient temperature, resulting in the generation of some gas bubbles, and stirred overnight. The obtained ethyl 3- { (1-chlorocarbonyl cyclopentyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } propanoate solution was used for the preparation of ethyl 3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) amino ] propanoate without isolation.
Similarly, the prepared ethyl 3- { (1-chlorocarbonyl cyclopentyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } propanoate solution was concentrated in vacuo to give an oil.
1H NMR(CDCl3)δ7.84-7.87(m,2H),6.97-7.12(m,6H),4.10(q,J=7.2 Hz,2H),3.55-3.59(m,2H),2.68-2.72(m,2H),2.47-2.53(m,2H),1.95-2.02(m,2H),1.71-1.76(m,4H),1.24(t,J=7.2 Hz,3H)。
G)3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) amino ] propanoic acid ethyl ester
A solution of 1.37g (19.7mmol,1.3 equivalents) hydroxylamine hydrochloride in 9.2ml (114mmol,7.5 equivalents) anhydrous pyridine at 0 ℃ was treated with 5.8ml (45mmol,3.0 equivalents) trimethylsilyl chloride resulting in the precipitation of a white solid. The mixture was heated to ambient temperature overnight. The mixture was then cooled to 0 ℃ and treated with a solution of 7.54g (15.1mmol) of ethyl 3- { (1-chlorocarbonyl cyclopentyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } propanoate in 73ml of dichloromethane prepared as described above without isolation, resulting in an exotherm to about 8 ℃. The mixture was stirred at 0 ℃ for 30 minutes and at ambient temperature for about one hour. The reaction was then treated with 50ml of 2N aqueous hydrochloric acid and stirred at ambient temperature for one hour. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 2N aqueous hydrochloric acid (2X 50ml) and water (50 ml). The dichloromethane solution of ethyl 3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoyl cyclopentyl) amino ] propanoate is used for preparing 3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoyl cyclopentyl) amino ] propanoic acid without separation. An aliquot was concentrated to a foam.
1H NMR(DMSO-d6)δ10.37(s,1H),8.76(s,1H),7.74-7.79(m,2H),7.24-7.30(m,2H),7.14-7.20(m,2H),7.01-7.05(m,2H),3.99(q,J=7.1 Hz，2H),3.42-3.47(m,2H),2.62-2.67(m,2H),2.16-2.23(m,2H),1.77-1.85(m,2H)，1.43-1.52(m,4H),1.13(t,J=7.1 Hz,3H)。
Similarly, the prepared solution was concentrated in vacuo to give 6.71g (89%) of ethyl 3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) amino ] propionate as a hard dry foam.
H)3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) amino ] propanoic acid
A solution of 7.48g (15.1mmol) of ethyl 3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) amino ] propanoate in dichloromethane was concentrated by rotary evaporation while adding 75ml of toluene. The solution was treated with 75ml of water, cooled to 0 ℃ and treated with 6.05g (151mmol,10 equivalents) of sodium hydroxide particles for 10 minutes with vigorous stirring. The mixture was stirred at 0 ℃ for 15 minutes and heated to ambient temperature over one hour. The aqueous phase is separated, diluted with 7.5ml of tetrahydrofuran, cooled to 0 ℃ and treated with 33ml of 6N aqueous hydrochloric acid for 20 minutes. The mixture is stirred with 75ml of ethyl acetate at 0 ℃ to ambient temperature, the ethyl acetate phase is separated and washed with water. The ethyl acetate solution was slowly treated with 150ml of hexane at ambient temperature resulting in precipitation of a solid which was stirred overnight. Filtration afforded 5.01g of 3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) amino ] propanoic acid as a white solid (71% yield from 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid).
1H NMR (DMSO-d6)δ12.32(s,1H),10.43(s,1H),8.80(s,1H),7.82(d,J=8.6 Hz,2H),7.28-7.35(m,2H),7.20-7.26(m,2H),7.08(d,J=8.9 Hz,2H),3.44-3.49(m,2H),2.61-2.66(m,2H),2.24-2.29(m,2H),1.86-1.90(m,2H),1.54-1.55(m,4H). mp 162.9-163.5℃(dec)。
Example 2
3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino ] propanoic acid
A)4- [ N- (diphenylmethylene) amino ] tetrahydropyran-4-carboxylic acid benzyl ester
To a suspension of sodium hydride (6.56g, 0.164mol) in ethylene glycol dimethyl ether (150ml) was added dropwise a solution of N- (diphenylmethylene) glycine benzyl ester (0.07398mol) in ethylene glycol dimethyl ether (50ml) at 0 ℃ via an addition funnel. To this ethylene glycol dimethyl ether solution was then added a solution of 2-bromoethyl ether (23.21g,0.090mol) in ethylene glycol dimethyl ether (50ml), in 10ml portions, over a period of about 5 minutes. The ice bath was removed and the reaction was stirred at room temperature for 16 hours. The mixture was diluted with diethyl ether and washed with water. The aqueous layer was extracted with diethyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give the crude product. Purification by silica gel chromatography eluting with 4L of 5% ethyl acetate/hexane followed by 4L of 10% ethyl acetate/hexane afforded benzyl 4- [ N- (diphenylmethylene) amino ] tetrahydropyran-4-carboxylate as a yellow clear oil.
(B) 4-Aminotetrahydropyran-4-carboxylic acid benzyl ester
To a solution of benzyl 4- [ N- (diphenylmethylene) amino ] tetrahydropyran-4-carboxylate (0.047mol) in diethyl ether (120ml) was added 1M aqueous hydrochloric acid (100 ml). The mixture was stirred vigorously at room temperature for 16 hours. The layers were separated and the aqueous layer was washed with diethyl ether. The aqueous layer was adjusted to pH 10 with dilute aqueous ammonium hydroxide and extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated to give benzyl 4-aminotetrahydropyran-4-carboxylate.
(C)4- [4- (4-fluorophenoxy) benzenesulfonylamino ] tetrahydropyran-4-carboxylic acid benzyl ester
To a solution of benzyl 4-aminotetrahydropyran-4-carboxylate (0.0404mol) in N, N-dimethylformamide (40ml) was added triethylamine (5.94ml, 0.043 mol). To the above solution was added solid 4- (4-fluorophenoxy) benzenesulfonyl chloride (12.165g, 0.0424mol) in portions. The resulting mixture was stirred at room temperature for 16 hours, then most of the solvent was evaporated under vacuum. The residue was distributed between saturated sodium bicarbonate solution and dichloromethane. The aqueous layer was separated and extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent under vacuum gave crude benzyl 4- [4- (4-fluorophenoxy) benzenesulfonylamino ] tetrahydropyran-4-carboxylate. Purification by flash chromatography on silica eluting with 25% ethyl acetate/hexane followed by 50% ethyl acetate/hexane afforded benzyl 4- [4- (4-fluorophenoxy) benzenesulfonylamino ] tetrahydropyran-4-carboxylate.
D) Benzyl 4- { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } tetrahydropyran-4-carboxylate
The product of the previous step (53.2mmol) was treated with 10.8ml (106mmol,2 equiv.) of ethyl propiolate in 200ml dry tetrahydrofuran at 1 ℃ with 53.2ml (53.2mmol,1 equiv.) of tetrabutylammonium fluoride in tetrahydrofuran (1M) for 45 min. The resulting solution was slowly heated to ambient temperature and stirred overnight. Toluene was used instead of tetrahydrofuran under reduced pressure, and the toluene solution was washed with water and brine, diluted to 600ml with toluene, stirred with 90g of silica gel for three hours, filtered and concentrated to give the title compound.
E)4- { (2-Ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } tetrahydropyran-4-carboxylic acid
A solution of the product of step D (4.4mmol) in 25ml of ethanol was treated with 2.5g of a 10% palladium-carbon catalyst wetted with 50% water and shaken under 53psi of hydrogen for 21 hours. The catalyst was removed by filtration and washed with ethanol (4X 25 ml). The filtrate and washings were combined and concentrated in vacuo to give the crude product.
F)3- { (4-Chlorocarbonyltetrahydropyran-4-yl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } propanoic acid ethyl ester
A solution of the product of step E (15.1mmol) in 73ml of dichloromethane was treated with 1.4ml (17mmol,1.1 equiv.) of oxalyl chloride and 0.02ml (0.3mmol,0.02 equiv.) of dimethylformamide at ambient temperature, resulting in some bubbling and stirring overnight. The resulting solution of the title compound was used in step G without isolation.
G)3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino ] propanoic acid ethyl ester
A solution of hydroxylamine hydrochloride (19.7mmol,1.3 equivalents) in 9.2ml (114mmol,7.5 equivalents) of anhydrous pyridine was treated with 5.8ml (45mmol,3.0 equivalents) of trimethylsilyl chloride at 0 deg.C, resulting in the precipitation of a white solid. The mixture was heated to ambient temperature overnight. The mixture was then cooled to 0 ℃ and treated with a solution of the product of step F (15.1mmol) in 73ml of dichloromethane, resulting in an exotherm to about 8 ℃. The mixture was stirred at 0 ℃ for 30 minutes and at ambient temperature for about one hour. The reaction was then treated with 50ml of 2N aqueous hydrochloric acid and stirred at ambient temperature for one hour. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 2N aqueous hydrochloric acid (2X 50ml) and water (50 ml). A solution of the title compound in dichloromethane was used in the following procedure.
H)3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino ] propanoic acid
A solution of 15.1mmol of the product of step G in dichloromethane was concentrated by rotary evaporation while 75ml of toluene were added. The solution was treated with 75ml of water, cooled to 0 ℃ and treated with 6.05g (151mmol,10 equivalents) of sodium hydroxide particles for 10 minutes with vigorous stirring. The mixture was stirred at 0 ℃ for 15 minutes and heated to ambient temperature over one hour. The aqueous phase is separated, diluted with 7.5ml of tetrahydrofuran, cooled to 0 ℃ and treated with 33ml of 6N aqueous hydrochloric acid for 20 minutes. The mixture is stirred with 75ml of ethyl acetate at 0 ℃ to ambient temperature, the ethyl acetate phase is separated and washed with water. The ethyl acetate solution was concentrated to give the title compound.
Example 3
3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (3-hydroxycarbamoyl-8-oxabicyclo [3.2.1] oct-3-yl) amino ] propanoic acid
A) Benzyl 3- (diphenylmethyleneamino) -8-oxabicyclo [3.2.1] octane-3-carboxylate
To a suspension of sodium hydride (0.41g,17.1mmol) in N, N-dimethylformamide (50ml) was added dropwise a solution of benzyl N-diphenylmethyleneglycinate (7.8mmol) in N, N-dimethylformamide (50m1) at 0 ℃. After stirring for 30 minutes at room temperature, a solution of cis-2, 5-bis (hydroxymethyl) tetrahydrofuran xylene sulfonate (4.1g,9.3mmol), prepared by literature methods such as JOC,47, 2429-propan 2435(1982), in N, N-dimethylformamide (50ml) was added dropwise. The reaction mixture was gradually heated to 100 ℃ in an oil bath and stirred at this temperature overnight. The solvent was evaporated under vacuum and the residue was dissolved in water and extracted twice with diethyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give the crude product.
(B) Benzyl 3-amino-8-oxabicyclo [3.2.1] octane-3-carboxylate hydrochloride
A biphasic mixture of benzyl 3- (diphenylmethyleneamino) -8-oxabicyclo [3.2.1] octane-3-carboxylate (3.9mmol) in 1N aqueous hydrochloric acid (100ml) and diethyl ether (100ml) was stirred at room temperature overnight. The aqueous layer was concentrated to give the title compound.
(C) Benzyl 3-exo- [4- (4-fluorophenoxy) benzenesulfonylamino ] -8-oxabicyclo [3.2.1] octane-3-carboxylate
Benzyl 3-amino-8-oxabicyclo [3.2.1] octane-3-carboxylate hydrochloride (2.9mmol), 4- (4-fluorophenoxy) benzenesulfonyl chloride (923mg,3.2mmol) and triethylamine (0.9ml,6.5mmol) in N, N-dimethylformamide (45ml) were stirred at room temperature overnight. The solvent was removed under vacuum and the residue was dissolved in saturated aqueous sodium bicarbonate. After two extractions with dichloromethane, the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to give a brown oil. The title compound was isolated by silica chromatography using 1% methanol in dichloromethane as eluent.
D) Benzyl 3- { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } -8-oxabicyclo [3.2.1] octane-3-carboxylate
The product of the previous step (53.2mmol) was treated with 10.8ml (106mmol,2 equiv.) of ethyl propiolate in 200ml dry tetrahydrofuran at 1 ℃ with 53.2ml (53.2mmol,1 equiv.) of tetrabutylammonium fluoride in tetrahydrofuran (1M) for 45 min. The resulting solution was slowly heated to ambient temperature and stirred overnight. Toluene was used instead of tetrahydrofuran under reduced pressure, and the toluene solution was washed with water and brine, diluted to 600ml with toluene, stirred with 90g of silica gel for three hours, filtered and concentrated to give the title compound.
E)3- { (2-Ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } -8-oxabicyclo [3.2.1] octane-3-carboxylic acid
A solution of the product of step D (4.4mmol) in 25ml of ethanol was treated with 2.5g of a 10% palladium-carbon catalyst wetted with 50% water and shaken under 53psi of hydrogen for 48 hours. The catalyst was removed by filtration and washed with ethanol (4X 25 ml). The filtrate and washings were combined and concentrated in vacuo to give the crude product.
F)3- { (3-Chlorocarbonyl-8-oxabicyclo [3.2.1] oct-3-yl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } propanoic acid ethyl ester
A solution of the product of step E (15.1mmol) in 73ml of dichloromethane was treated with 1.4ml (17mmol,1.1 equiv.) of oxalyl chloride and 0.02ml (0.3mmol,0.02 equiv.) of dimethylformamide at ambient temperature, resulting in some bubbling and stirring overnight. The resulting solution of the title compound was used in step G without isolation.
G)3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (3-hydroxycarbamoyl-8-oxabicyclo [3.2.1] oct-3-yl) amino ] propanoic acid ethyl ester
A solution of hydroxylamine hydrochloride (19.7mmol,1.3 equivalents) in 9.2ml (114mmol,7.5 equivalents) of anhydrous pyridine was treated with 5.8ml (45mmol,3.0 equivalents) of trimethylsilyl chloride at 0 deg.C, resulting in the precipitation of a white solid. The mixture was heated to ambient temperature overnight. The mixture was then cooled to 0 ℃ and treated with a solution of the product of step F (15.1mmol) in 73ml of dichloromethane, resulting in an exotherm to about 8 ℃. The mixture was stirred at 0 ℃ for 30 minutes and at ambient temperature for about one hour. The reaction was then treated with 50ml of 2N aqueous hydrochloric acid and stirred at ambient temperature for one hour. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 2N aqueous hydrochloric acid (2X 50ml) and water (50 ml). A solution of the title compound in dichloromethane was used in the following procedure.
H)3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (3-hydroxycarbamoyl-8-oxabicyclo [3.2.1] oct-3-yl) amino ] propanoic acid
A solution of 15.1mmol of the product of step G in dichloromethane was concentrated by rotary evaporation while 75ml of toluene were added. The solution was treated with 75ml of water, cooled to 0 ℃ and treated with 6.05g (151mmol,10 equivalents) of sodium hydroxide particles for 10 minutes with vigorous stirring. The mixture was stirred at 0 ℃ for 15 minutes and heated to ambient temperature over one hour. The aqueous phase is separated, diluted with 7.5ml of tetrahydrofuran, cooled to 0 ℃ and treated with 33ml of 6N aqueous hydrochloric acid for 20 minutes. The mixture is stirred with 75ml of ethyl acetate at 0 ℃ to ambient temperature, the ethyl acetate phase is separated and washed with water. The ethyl acetate solution was concentrated to give the title compound.
Preparation 1
4- (4-fluorophenoxy) benzenesulfonic acid 4-fluorophenyl ester
A solution of 14.68g (0.131mol, 2.0 equivalents) of potassium tert-butoxide in 27ml of anhydrous N-methylpyrrolidone is treated with a solution of 15.39g (0.137mol,2.1 equivalents) of 4-fluorophenol in 27ml of anhydrous N-methylpyrrolidone at ambient temperature, resulting in a slight exotherm to 45 ℃. To the dark reaction mixture was slowly added a solution of 13.81g (0.065mol) 4-chlorobenzenesulfonyl chloride in 27ml anhydrous N-methylpyrrolidone, resulting in a slight exotherm to 44 ℃. The resulting mixture was stirred at room temperature for one hour and then at 130 ℃ for 11 hours. The cooled reaction mixture was treated with 162ml of water, seeded with a trace of 4-fluorophenyl 4- (4-fluorophenoxy) benzenesulfonate and granulated overnight at room temperature. The resulting solid was filtered to give 20.24g (85%) of 4-fluorophenyl 4- (4-fluorophenoxy) benzenesulfonate.
1H NMR(CDCl3)δ7.74(dd,J=7.0,2.0 Hz,2H),7.14-6.97(m,10H)。mp 78-83℃。
Preparation 2
4- (4-fluorophenoxy) benzenesulfonic acid sodium salt
To a slurry of 47.43g (0.131mol)4- (4-fluorophenoxy) benzenesulfonic acid 4-fluorophenyl ester in 475ml ethanol was added 13.09g (0.327mol,2.5 equivalents) sodium hydroxide particles. The mixture was heated to reflux for three hours and stirred at room temperature overnight. The resulting solid was filtered to give 37.16g (98%) of 4- (4-fluorophenoxy) benzenesulfonic acid sodium salt.
1H NMR(CD3OD)δ7.73-7.78(m,2H),7.05-7.13(m,2H),6.99-7.05(m,2H),6.90-6.95(m,2H)。
Preparation 3
4- (4-fluorophenoxy) benzenesulfonyl chloride
To a slurry of 15.0g (0.052mol) of 4- (4-fluorophenoxy) benzenesulfonic acid sodium salt in 150ml of anhydrous toluene were added 11.3ml (0.155mol, 3 eq) of thionyl chloride and 0.04ml (0.5mmol,0.01 eq) of dimethylformamide. The resulting mixture was stirred at room temperature for 48 hours, filtered through celite, and concentrated to 40ml under reduced pressure. This solution was used to prepare benzyl 1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclopentanecarboxylate without further purification.
5.0ml of the solution was concentrated to give 1.77g of 4- (4-fluorophenoxy) benzenesulfonyl chloride as an oil, corresponding to a yield of 96%.
1H NMR(CDCl3)δ7.92-7.97(m,2H),7.01-7.13(m,6H)。
A portion of the similarly prepared oil was crystallized from hexane, mp 80 ℃.
Example 4
Preparation 1
1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclopentanecarboxylic acid
1- [4- (4-fluorophenoxy) benzenesulfonylamino group]Benzyl cyclopentanecarboxylate (15g,32mmol) in 75ml THF was mixed with 75ml (150mmol)2N aqueous sodium hydroxide and stirred at reflux for 1 h. The reaction was cooled to ambient temperature and diluted with 100ml water and 100ml ethyl acetate. The pH of the aqueous phase was adjusted to pH 1.2 and the ethyl acetate layer was separated. The ethyl acetate layer was washed with 100ml of water and dried over magnesium sulfate. The ethyl acetate was extracted in vacuo and replaced with 75ml of methyl tert-butyl ether. The product was filtered and dried to give 11.16g (92%) of 1- [4- (4-fluorophenoxy) benzenesulfonylamino]Cyclopentanecarboxylic acid.1H NMR(CDCl3)□7.71-7.78(m,2H),6.88-7.04(m,6H),5.04(s,1H),2.01-2.13(m,2H),1.92-1.98(m,2H),1.44-1.68(m,4H)。
Preparation 2
1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclopentanecarboxylic acid tert-butyl ester
To 1- [4- (4-fluorophenoxy) benzenesulfonylamino group]A solution of cyclopentanecarboxylic acid (10.22g, 27mmol) in 100ml of dichloromethane was condensed with 40ml of isobutene at-78 ℃. Concentrated sulfuric acid (0.3ml) was added to the reaction solution, and the mixture was warmed to room temperature and stirred for 22 hours. The mixture was then washed with 3X 50ml of 2N NaOH and the organic layer was dried over magnesium sulfate and evaporated to give 11.17g (95%) of 1- [4- (4-fluorophenoxy) benzenesulfonylamino]Tert-butyl cyclopentanecarboxylate.1H NMR(CDCl3)□7.74-7.77(m,2H),6.85-7.13(m,6H),4.95(s,1H),1.92-2.02(m,2H),1.78-1.88(m,2H),1.50-1.65(m,4H),1.35(s,9H)。
Those skilled in the art will recognize numerous other strategies for synthesizing the reaction intermediates described herein. For example, esterification with isobutene can be carried out on a molecule,
then with, for example, QSO2The Cl moiety is thioalkylated. In addition, the tertiary butyl esters of the above structure are known to be readily prepared or may be commercially available.
Preparation 3
1- { (2-Ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid tert-butyl ester
To 1- [4- (4-fluorophenoxy) benzenesulfonylamino group at ambient temperature]To a mixture of tert-butyl cyclopentanecarboxylate (1.0g,2.3mmol) in 10ml of THF and 2.3ml (2.3mmol) of 1M tetrabutylammonium fluoride in THF was added 0.23ml (2.3mmol) of ethyl propiolate. After stirring for 1 hour, HPLC indicated the reaction was complete and stripped to dryness in vacuo. The residue was dissolved in 20ml of ethyl acetate, washed with 2X 10ml of water and the organic solution was stripped to give an oil. The oil is purified by silica gel chromatographyElution with 10% ethyl acetate/hexanes provided 0.95g (77% yield) of 1- { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) benzenesulfonyl]Amino } cyclopentanecarboxylic acid tert-butyl ester, as a colorless oil.1H NMR(CDCl3) Indicating a trans/cis ratio of 1.5: 1.
Trans □ 7.79.79-7.83 (m,2H),7.63(d, J =14 Hz,1H),6.89-7.05(m,4H),5.44(d, J =14 Hz,1H),4.08(q, J =7.1Hz, 1H),2.08-2.43(m,4H),1.63-1.80(m,4H),1.39(s,9H),1.22(t, J =7.1Hz,3H). Cis 7.62-7.69(m,2H),6.91-6.85(m,2H),6.55(d, J =8.1 Hz,1H),5.85(d, J =8.1 Hz,1H),3.81(q, J =7.2Hz, 2H),2.08-2.43, m,4H),1.19-1.25, m,4H),1.49(s,9H),1.11(q, J =7.2Hz,3H)
Preparation 4
1- { (2-Ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid tert-butyl ester
A solution of tert-butyl 1- { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylate (1.23g,2.3mmol) in 50ml ethanol containing 723mg of 5% Pd/C catalyst was hydrogenated at ambient temperature until the reaction was complete as indicated by HPLC. The catalyst was filtered and the filtrate evaporated to give an oil which was purified by chromatography on silica gel eluting with 105 ethyl acetate in hexane. Tert-butyl 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylate was isolated as a colorless oil (875mg, 71% yield).
1H NMR (CDCl3)□7.75-7.80(m,2H),6.86-7.01(m,6H),4.09(q,J=7.2,2H),3.44-3.48(m,2H),2.66-2.72,m,2H),2.09-2.15(m,2H),1.52-1.74,m,4H),1.43(s,9H),1.21(t,J=7.2 Hz,3H)
Preparation 5
Dicyclohexylammonium 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylate
A solution of tert-butyl 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylate (0.225g, 0.42mmol) in 4ml toluene was treated with methanesulfonic acid (0.06ml, 0.84mmol) at ambient temperature for 18 h. The solution was washed with aqueous sodium bicarbonate and evaporated to give a colourless oil. The oil was dissolved in 2ml ethanol and treated with dicyclohexylamine (0.084ml,0.42 mmol). The product dicyclohexylammonium 1- ((2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylate is filtered and dried to give 223mg (80% yield) of a white solid with the same HPLC retention time and NMR as the sample prepared from the benzyl ester route.

Claims (12)

1. A compound of the formula
Wherein R is1Is [ (A)1)CH2]c[(A2)CH2]b[(A3)CH2]aC-, wherein a, b and C are each 1; each A is1、A2And A3Independently selected from the group consisting of H, (C)1-C5) Alkyl and phenyl or substituted phenyl;
R2and R3Independently is (C)1-C6) Alkyl, or R2And R3Together form a three-to seven-membered cycloalkyl, pyran-4-yl ring or bicyclic ring of the formula
Wherein the asterisks indicate R2And R3A common carbon atom;
q is (C)1-C6) Alkyl, (C)6-C10) Aryl group, (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkyl, (C)6-C10) Aryloxy radical (C)1-C6) Alkyl, (C)6-C10) Aryloxy radical (C)6-C10) Aryl group, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)6-C10) Aryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryloxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryloxy (C)6-C10) Aryl group, (C)2-C9) Heteroaryloxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)6-C10) Aryl or (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)2-C9) A heteroaryl group;
wherein said (C)6-C10) Aryl group, (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkyl, (C)6-C10) Aryloxy radical (C)1-C6) Alkyl, (C)6-C10) Aryloxy radical (C)6-C10) Aryl group, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)6-C10) Aryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryloxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryloxy (C)6-C10) Aryl group, (C)2-C9) Heteroaryloxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)6-C10) Aryl or (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)2-C9) Each (C) of heteroaryl6-C10) Aryl or (C)2-C9) The heteroaryl moiety is optionally substituted on any additional ring carbon atom with one or more substituents independently selected from fluorine, chlorine, bromine, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, perfluoro (C)1-C3) Alkyl, perfluoro (C)1-C3) Alkoxy and (C)6-C10) An aryloxy group;
y is hydrogen or (C)1-C6) An alkyl group.
2. The compound of claim 1, wherein R2And R3Together form a cyclobutyl, cyclopentyl, pyran-4-yl ring or a bicyclic ring of formula
Wherein the asterisks indicate R2And R3A common carbon atom.
3. The compound of claim 1, wherein Q is 4- (4-fluorophenoxy) phenyl.
4. A process for the preparation of a compound of the formula
Wherein R is1Is [ (A)1)CH2]c[(A2)CH2]b[(A3)CH2]aC-, wherein a, b and C are each 1; each A is1、A2And A3Independently selected from the group consisting of H, (C)1-C5) Alkyl and phenyl or substituted phenyl;
R2and R3Independently is (C)1-C6) Alkyl, or R2And R3Together form a three-to seven-membered cycloalkyl, pyran-4-yl ring or bicyclic ring of the formula
Wherein the asterisks indicate R2And R3A common carbon atom;
q is (C)1-C6) Alkyl, (C)6-C10) Aryl group, (C)2-C9) Heteroaryl, (C)6-C10) Aryloxy radical (C)1-C6) Alkyl, (C)6-C10) Aryloxy radical (C)6-C10) Aryl group, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)6-C10) Aryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryloxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryloxy (C)6-C10) Aryl group, (C)2-C9) Heteroaryloxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)6-C10) Aryl or (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)2-C9) A heteroaryl group;
wherein said (C)6-C10) Aryl group, (C)2-C9) Heteroaryl, (C)6-C10) Aryloxy radical (C)1-C6) Alkyl, (C)6-C10) Aryloxy radical (C)6-C10) Aryl group, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)6-C10) Aryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryloxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryloxy (C)6-C10) Aryl group, (C)2-C9) Heteroaryloxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)6-C10) Aryl or (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)2-C9) Each (C) of heteroaryl6-C10) Aryl or (C)2-C9) The heteroaryl moiety is optionally substituted on any additional ring carbon atom with one or more substituents independently selected from fluorine, chlorine, bromine, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, perfluoro (C)1-C3) Alkyl, perfluoro (C)1-C3) Alkoxy and (C)6-C10) An aryloxy group;
y is (C)1-C6) An alkyl group;
the process comprises reacting a compound of the formula
Wherein R is1、R2、R3And Q is as defined above;
with a compound of the formula
Wherein Y is (C)1-C6) An alkyl group.
5. The process according to claim 4, wherein said base is tetrabutylammonium fluoride.
6. The process according to claim 4, wherein said solvent is tetrahydrofuran.
7. The method according to claim 4, further comprising the step of reducing said compound of the formula
Wherein R is1、R2、R3Y and Q are as defined in claim 4;
to form a compound of the formula
Wherein R is1、R2、R3Y and Q are as defined above.
8. The process of claim 7 wherein said reducing agent is hydrogen on a catalyst selected from the group consisting of platinum oxide or Raney nickel or on a supported catalyst selected from the group consisting of palladium-carbon or platinum-carbon.
9. The process according to claim 7, wherein the reduction is carried out in ethanol as a solvent.
10. The process according to claim 7, further comprising hydrolyzing said compound of the formula under acidic conditions
Wherein R is1、R2、R3Y and Q are as defined in claim 7 to form a compound of the formula
Wherein R is2、R3Y and Q are as defined above.
11. The method of claim 4, comprising:
(a) first step of further hydrolyzing the compound of the formula
Wherein R is1、R2、R3Y and Q are as defined in claim 4 to form a compound of the formula
Wherein R is2、R3Y and Q are as defined above; and
(b) a second step of further reducing said compound (a) with a reducing agent to form a compound of the formula
Wherein R is2、R3Y and Q are as defined above.
12. The process according to claim 11, wherein said reducing agent is hydrogen on a catalyst selected from the group consisting of platinum oxide or raney nickel or a supported catalyst selected from the group consisting of palladium-carbon or platinum-carbon.
HK01106638.4A 1998-04-10 1999-04-09 Process for alkylating hindered sulfonamides useful in the production of matrix metal-loproteinase inhibitors HK1036270A (en)

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