Manufacturing method of piperidine derivative

专利摘要:
The present invention discloses a process for preparing piperidine derivatives of formula (I) or (II). (Wherein n is 0 or 1; R 1 is hydrogen or hydroxy; R 2 is hydrogen; or when n is 0, R 1 and R 2 together form a second bond between the carbon atoms containing R 1 and R 2 , Provided that when n is 1, R 1 and R 2 are each hydrogen; R 3 is -COOH or -COOR 4 ; R 4 is an alkyl or aryl moiety; A, B and D are substituents of each ring, each of which may be the same or different and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents) One method comprises providing a regioisomer of Formula III, and converting the regioisomer into a piperidine derivative compound of the invention having a keto group using a piperidine compound. (Wherein Z is —CG 1 G 2 G 3 , wherein Formula IV or V; m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of O, S and NR 5 ; G 1 , G 2 and G 3 are the same or different and are selected from the group consisting of OR 8 , SR 8 and NR 8 R 9 ; X 3 is halogen, OR 15 , SR 15 , NR 15 R 16 , OSO 2 R 15 or NHSO 2 R 15 ; R 6 and R 7 are the same or different and are selected from the group consisting of hydrogen, alkyl moiety, aryl moiety, OR 8 , SR 8 and NR 8 R 9 ; R 5 , R 8 , R 9 , R 15 and R 16 are the same or different and are selected from the group consisting of hydrogen, alkyl residues and aryl residues) Another method for producing a piperidine derivative compound provides an α, α-disubstituted-methylbenzene derivative having the formula VI, wherein the α, α-disubstituted-methylbenzene derivative is converted by using a piperidine compound Preparing a ferridine derivative compound. (Wherein X 1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, substituted sulfonic acid ester or substituent useful for organometallic coupling reactions) In another aspect of the present invention, there is provided a 4- (α, α-disubstituted) -toluic acid derivative having the general formula (VII), which includes preparing a piperidine derivative compound by converting it using a piperidine compound. (Wherein X 2 is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR 10 ; Residues of the formula -SR 10 ; Or an amine; R 10 is selected from the group consisting of hydrogen, alkyl residues and aryl residues)
公开号:KR20000064507A
申请号:KR1019980704760
申请日:1996-12-19
公开日:2000-11-06
发明作者:토마스 이. 담브라；게리 엠. 필링
申请人:알바니 몰레큘라 리써치, 인크.；
IPC主号:

专利说明:

Process for preparing piperidine derivative
Terfenadine, 1- (pt-butylphenyl) -4- [4 '-(α-hydroxydiphenylmethyl) -1'-piperidinyl] -butanol is an intact antihistamine. It has also been reported as a specific H ¹ -receptor antagonist without any anticholine, antiserotonin and antiadrenergic effects both in vitro and in vivo (D. McTavish, K. L. Orphans (KL). Goa), M. Ferrill, Drugs, 1990, 39, 552; CR Kingsolving, NL Monroe, AA Carr , Pharmacologist, 1973, 15, 221; J.K Woodward, NL Munro, Arzneim-Forsch, 1982, 32, 1154; K.V. Mann, K. (See KJ Tietze, Clin. Pharm., 1989, 6, 331). Much effort has been made to investigate the structural activity relationship of terpenadine analogs, which has been shown in many US patents that disclose similar compounds and similar structures.
US Patent No. 3,867,956 to Zivkovic,
US Patent No. 3,806,526 to Karl et al.,
US Patent No. 3,829,433 to Karl et al.,
US Patent No. 3,862,173 to Karl et al.,
US Patent No. 3,878,217 to Karl et al.,
U.S. Patent No. 3,922,276 to Duncan et al.,
US Patent No. 3,931,197 to Karl et al.,
US Patent No. 3,941,795 to Karl et al.,
US Patent No. 3,946,022 to Karl et al.,
U.S. Patent No. 3,956,296 to Duncan et al.,
3,965,257 to Carl et al.,
Fawcett et al. US Pat. No. 4,742,175
During metabolic studies in animals and humans, terfenadine has been shown to undergo extensive hepatic first-pass metabolism and cannot be detected in plasma without the use of highly sensitive assays after conventional administration. The specific soy cytochrome P-450 enzyme is a major metabolite, 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-, which is also known as terpenadine as a terpenadine carboxylic acid metabolite. Hydroxybutyl] -α-α-dimethylphenylacetic acid. This metabolite is easily searchable in plasma and is shown in the active form of terpenadine administered orally.
Reported side effects of terpenadine are cardiac arrhythmias (ventricular tachyarrhythmia, torsade de points, ventricular fibrillation), sedation, GI fatigue, dry mouth, constipation and / or diarrhea. The most serious and life-threatening is cardiac arrhythmia, which is related to terpenadine's ability to delay cardiac QT intervals and has been reported only in patients receiving terpenadine while suffering from liver disease, or in patients receiving the fungal ketoconazole or antibiotic erythromycin. . As a result of this adverse effect, in 1992 the FDA ordered terpenadine to include a warning label. Although OTC preparations of terpenadine have been developed with significant significance, the very serious side effects observed in some patients will be an important obstacle to regulatory approval.
Since the cardiac side effects of terfenadine have been reported not only in patients taking antibiotics known to inhibit the enzyme function of the liver, but also in patients with impaired liver function, the cardiac side effects are not due to the accumulation of terpenadine carboxylic acid metabolites, but terpenadine. Presumably due to the accumulation of. Patch clamp investigations in isolated feline ventricular myocytes support the argument that terpenadine, not a carboxylic acid metabolite, is responsible for cardiac side effects. Terfenadine inhibits at least 90% of delayed rectified potassium flow at 1 μM concentration. Terpenadine carboxylic acid metabolites show little effect on potassium flow to concentrations below 5 μM in this assay (RL Woosley, Y. Chen, J.P. JP Fieman and RA Gillis, JAMA 1993, 269, 1532. Since inhibition of ion transport is linked to cardiac abnormalities such as arrhythmias, it can be seen from the results that terpenadine carboxylic acid does not cause cardiac arrhythmias even at doses at which the side effects caused by terfenadine itself are extremely threatening.
Caravastin, 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-oxobutyl] -α, α-dimethylphenylacetic acid is 1- (pt-butylphenyl) -4 Carboxylic acid metabolite of evastin which is-[4 '-( -Diphenylmethoxy) -1'-piperidinyl] -butanol. Both compounds have strong selective histamine H ¹ -receptor blocker and calcium antagonist properties and have proven useful in the treatment of various respiratory, allergic and cardiovascular disease states.
These compounds relax bronchial and cardiac smooth muscle in vitro and in vivo and inhibit the contractile effects of noradrenaline, potassium ions and various other agonist agents. These compounds also inhibit the response of intestinal and organ preparations to histamine, acetylcholine and barium chloride to prevent bronchial contractions caused by histamine aerosols in guinea pigs administered orally at doses less than 1 mg per kg body weight of the animal. . They also have anaphylactic properties in mice, inhibit skin damage to several anaphylactic mediators (histamine, 5-hydroxytrytamine, pradikinin, LCD _4, etc.), and Schultz-Dale responses in sensitive guinea pigs. Antagonize
Piperidine derivatives associated with terpenadine carboxylic acid metabolites are disclosed in the following US patents.
US Patent No. 4,254,129 to Karl et al.,
US Patent No. 4,254,130 to Karl et al.,
US Patent No. 4,285,957 to Karl et al.,
US Patent No. 4,285,958 to Karl et al.
In these patents, 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetic acid and related compounds are substituted with Piperidine derivatives

Ω-haloalkyl substituted phenyl ketone of the formula

Prepared by alkylation with the substituents halo, R ¹ , R ² , n, Z and R ⁶ described in column 6 of US Pat. No. 4,254,130.
In a similar manner, US Pat. No. 4,550,116 to Soto et al. Discloses a piperidine derivative associated with curevastin by reacting a ω-haloalkyl substituted phenyl ketone with a substituted hydroxypiperidine derivative of the general formula Methods of making are described.

US Pat. No. 4,254,130 discloses suitable straight or branched chain lower alkyl C _1-6 esters of α-α-dimethylphenylacetic acid with compounds of the formula

(Where halo and m are described in column 11 of US Pat. No. 4,254,129) under the general conditions of Friedel-Crafts acylation to react ω-haloalkyl substituted phenyl ketones, wherein Z Is hydrogen). This reaction is carried out in carbon disulfide as a preferred solvent.
Other procedures for preparing terpenadine carboxylic acid metabolites are disclosed in PCT applications WO95 / 00492, WO94 / 03170 and WO95 / 00480.
The present invention is directed to an improved process for the preparation of terfenadine carboxylic acid metabolites and curevastin derivatives.
Summary of the Invention
The present invention relates to a process for preparing piperidine derivative compounds of the formula

or

(In each formula above,
n is 0 or 1;
R ¹ is hydrogen or hydroxy;
R ² is hydrogen; or
when n is 0, R ¹ and R ² together form a second bond between the carbon atoms containing R ¹ and R ² ,
Provided that when n is 1, R ¹ and R ² are each hydrogen;
R ³ is -COOH or -COOR ⁴ ;
R ⁴ is an alkyl or aryl moiety;
A, B and D are substituents of each ring, each of which may be the same or different and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents)
In one aspect of the present invention, piperidine derivative compounds are prepared by providing a regioisomer having the formula:

(Wherein
Z is -CG ¹ G ² G ³ ,
or ego;
m is an integer from 1 to 6;
Q and Y are the same or different and are selected from the group consisting of O, S and NR ⁵ ;
G ¹ , G ² and G ³ are the same or different and are selected from the group consisting of OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
X ³ is halogen, OR ¹⁵ , SR ¹⁵ , NR ¹⁵ R ¹⁶ , OSO ₂ R ¹⁵ or NHSO ₂ R ¹⁵ ;
R ⁶ and R ⁷ are the same or different and are selected from the group consisting of hydrogen, an alkyl residue, an aryl residue, OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
R ⁵ , R ⁸ , R ⁹ , R ¹⁵ and R ¹⁶ are the same or different and are selected from the group consisting of hydrogen, alkyl residues and aryl residues)
The regioisomer is then converted to a piperidine derivative with a keto group using a piperidine compound.
In another aspect of the present invention, there is provided an α, α-disubstituted-methylbenzene derivative having the formula: wherein the α, α-disubstituted-methylbenzene derivative is a piperidine compound under conditions effective to produce a piperidine derivative compound The piperidine derivative compounds are prepared by conversion using.

(Wherein
X ¹ is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, alkylhalo silicon, trialkyl silicon, substituted sulfonic acid ester or substituent useful for organometallic coupling reactions)
In another aspect of the present invention, a 4- (α, α-disubstituted) -toluic acid derivative having the following formula is provided, and the 4- (α, α-disubstituted) toluic acid derivative is used to produce a piperidine derivative compound. Piperidine derivative compounds are prepared by conversion using piperidine compounds under effective conditions.

(Wherein
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ¹⁰ is selected from the group consisting of hydrogen, alkyl residues and aryl residues)
The present invention also relates to regioisomers having the formula:

The present invention also relates to a process for preparing the regioisomer having the formula

In one aspect of the invention, the method for preparing the regioisomer is α, α-disubstituted-methylbenzene derivative having the formula

(Wherein
X ¹ is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, alkyl halo silicon, trialkyl silicon, substituted sulfonic acid ester or substituent useful for organometallic coupling reactions) under conditions effective to produce the regioisomer Compound having the formula

or

(Wherein
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ¹⁰ is selected from the group consisting of hydrogen, alkyl moieties and aryl moieties).
In another aspect of the present invention, the method for preparing the regioisomer is 4- (α, α-disubstituted) -toluic acid derivative having the formula

(Wherein
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ¹⁰ is selected from the group consisting of hydrogen, an alkyl moiety and an aryl moiety)

(Wherein
X ¹ comprises halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, alkyl halo silicon, trialkyl silicon, substituted sulfonic acid esters or substituents useful in organometallic coupling reactions).
In still another aspect of the present invention, a method for preparing a regioisomer provides an α, α-disubstituted regioisomer precursor having the formula: Methylation underneath.

The present invention also relates to 4- (α, α-disubstituted) -toluic acid derivatives and 4- (α, α-disubstituted) -toluic acid derivatives each having the formulas

And

(Wherein
Z is -CG ¹ G ² G ³ ,
or ego;
m is an integer from 1 to 6;
Q and Y are the same or different and are selected from the group consisting of O, S and NR ⁵ ;
G ¹ , G ² and G ³ are the same or different and are selected from the group consisting of OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ⁶ and R ⁷ are the same or different and are selected from the group consisting of hydrogen, an alkyl residue, an aryl residue, OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
R ⁵ , R ⁸ , R ⁹ and R ¹⁰ are the same or different and are selected from the group consisting of hydrogen, alkyl residues and aryl residues;
A is a ring substituent, each of which may be the same or different and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents)
The present invention relates to a process for the preparation of piperidine derivatives.
The present invention relates to a process for preparing piperidine derivative compounds having the formula: or salts thereof.

or

(In each formula above,
n is 0 or 1;
R ¹ is hydrogen or hydroxy;
R ² is hydrogen; or
when n is 0, R ¹ and R ² together form a second bond between the carbon atoms containing R ¹ and R ² ,
Provided that when n is 1, R ¹ and R ² are each hydrogen;
R ³ is -COOH or -COOR ⁴ ;
R ⁴ is an alkyl or aryl moiety;
A, B and D are substituents of each ring, each of which may be the same or different and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents)
These piperidine derivative compounds may be in the form of 4-diphenylmethylpiperidine derivatives represented by the following formulas.

or

(Wherein
A, B, D and R ³ are as defined above)
Piperidine derivative compounds also include 4- (hydroxydiphenylmethyl) piperidine derivatives according to the formula:

or

(Wherein
A, B, D and R ³ are as defined above)
Another useful piperidine derivative compound class is 4-diphenylmethylenepiperidine derivatives according to the formula:

or

(Wherein
A, B, D and R ³ are as defined above)
Another useful piperidine derivative compound class is 4-diphenylmethoxypiperidine derivatives having the formula:

or

(Wherein
A, B, D and R ³ are as defined above)
Examples of R ⁴ include substitutions comprising methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, benzyl and 4-methylbenzel groups Substituted or unsubstituted aryl groups including unsubstituted, straight or branched chain alkyl groups and phenyl, tolyl and xylyl groups.
Examples of the compound prepared by the method of the present invention are as follows.
4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetic acid;
4- [4- [4- (diphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetic acid;
4- [4- [4- (diphenylmethylene) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetic acid;
4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethyl-3-hydroxybenzeneacetic acid;
4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethyl-2-hydroxybenzeneacetic acid;
4- [4- [4- (diphenylmethylene) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethyl-3-hydroxybenzeneacetic acid;
4- [4- [4- (diphenylmethylene) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetic acid;
Ethyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetate;
n-pentyl 4- [4- [4- (diphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetate;
Ethyl 4- [4- [4- (diphenylmethylene) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetate;
Methyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetate;
Ethyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethyl- (3-hydroxybenzene) acetate;
n-propyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethyl- (2-hydroxybenzene) acetate;
n-hexyl 4- [4- [4- (diphenylmethylene) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethyl- (3-hydroxybenzene) benzeneacetate;
Ethyl 4- [4- [4- (diphenylmethylene) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetate;
4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetic acid;
4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethyl-3-hydroxybenzeneacetic acid;
4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethyl-2-hydroxybenzeneacetic acid;
4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethyl-3-hydroxybenzeneacetic acid;
4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetic acid;
n-pentyl 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetate;
Ethyl 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetate;
Ethyl 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethyl- (3-hydroxybenzene) acetate;
n-propyl 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethyl- (2-hydroxybenzene) acetate;
n-hexyl 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethyl- (3-hydroxybenzene) acetate;
Ethyl 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzeneacetate.
Particularly preferred compounds are those of the formula



And

Optionally, as shown in the following formulae, all of the diphenyl groups of the piperidine compound may be alkyl (eg methyl) substituted para position relative to methylene.



or

The compound prepared by the process of the invention may be a pharmaceutically acceptable salt in the form of an inorganic or organic acid or base addition salt of said compounds. Suitable inorganic acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Suitable organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, cyclic acid, ascorbic acid, maleic acid, hydroxymaleic acid, dihydroxymaleic acid, benzoic acid, phenyl Carboxylic acids such as acetic acid, 4-aminobenzoic acid, anthranilic acid, cinnamic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid and mandelic acid. Sulphonic acids such as methanesulfonic acid, ethanesulfonic acid and β-hydroxyethane-sulfonic acid are also suitable acids. Non-toxic salts formed with inorganic and organic bases and compounds of the formulas include, for example, alkali metals such as sodium, potassium and lithium, alkaline earth metals such as calcium and magnesium, light metals of group IIIA such as aluminum, primary and secondary Or tertiary amines such as cyclohexylamine, ethylamine, pyridine, methylaminoethanol and piperazine. These salts are prepared, for example, by conventional means for treating piperidine derivative compounds of the formula: with a suitable acid or base.

or

(In each formula above,
A, B, D, n, R ¹ , R ² and R ³ are as defined above)
Piperidine derivative compounds prepared by the methods of the invention can be used as biologically active ingredients in pharmaceutical compositions. These compounds are useful as antihistamines, anti-allergic and bronchodilators. They may be administered alone or in combination with a suitable carrier and may be in solid or liquid form such as tablets, capsules, powders, solutions, suspensions or emulsions.
Compounds prepared by the methods of the invention may be administered orally, parenterally, for example, subcutaneously, transdermally, intramuscularly, intraperitoneally, intranasally, or by application to mucous membranes such as nose, throat and bronchial tubes. can do. The application to the mucous membrane can be carried out in the form of a spray or dry powder of aerosol spray containing small particles of the compound of the present invention.
The amount of compound administered varies depending on the patient and the mode of administration and can be any effective amount. The amount of compound administered can vary over a wide range providing in a unit dose about 0.01 to 20 mg / kg body weight of the patient in an amount effective to achieve the desired effect. For example, the desired antihistamine, antiallergic and bronchodilator effects can be obtained by consuming one to four unit dosage forms, such as tablets containing 1 to 50 mg of the compound of the invention.
Solid unit dosage forms can be of conventional type. Such solid forms may be capsules of the general gelatin type containing a compound of the invention and a carrier, for example a lubricant and an inert filler such as lactose, sucrose or corn starch. In another embodiment, a compound of the invention is lactose, sucrose or corn combined with a binder such as acacia, corn starch or gelatin, a disintegrant such as corn starch, potato starch or alginic acid and a lubricant such as stearic acid or magnesium stearate. Tableting is carried out using conventional purification base materials such as starch.
The compounds prepared according to the invention can also be administered in injectable doses by solutions or suspensions of the compounds of the invention in pharmaceutical carriers and physiologically acceptable diluents. Such carriers include sterile liquids, such as water and oils, with or without surfactants and other pharmaceutically acceptable auxiliaries. Examples of oils are petroleum, animal oils, vegetable oils or synthetic oils, for example peanut oil, soybean oil or mineral oil. In general, water, menstrual water, glucose and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are preferred for liquid carriers, in particular for injectable solutions.
For use as aerosols, the compounds in solution or suspension can be packaged in pressurized aerosol containers with suitable propellants, for example hydrocarbon propellants such as propane, butane or isobutane and conventional auxiliaries. These compounds may be administered in unpressurized form such as nebulizers or nebulizers.
The compounds prepared according to the invention can be used to treat incubated animals, birds and mammals. Examples include humans, cats, dogs, horses, sheep, cows, pigs, lambs, mice, mice, and guinea pigs.
According to one aspect of the present invention, a piperidine derivative compound is prepared by providing a regioisomer of the formula and converting the regioisomer into a piperidine derivative compound of the present invention having a keto group using the piperidine compound.

The piperidine derivative compound having the resulting keto group can then be converted to the piperidine compound having a hydroxyl group by reduction.
A is a substituent of the ring, each of which may be the same or different and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents.
X ³ is halogen, hydroxy or alkoxy, thiol of formula OR ¹⁵ or alkylthio derivative of formula SR ¹⁵ , amine of formula NR ¹⁵ R ¹⁶ , sulfonic acid ester of formula OSO ₂ R ¹⁵ , such as chloride, bromide or iodide Methanesulfonate or tosylate) or sulfonamides of the formula NHSO ₂ R ¹⁵ . R ¹⁵ and R ¹⁶ are the same or different and are hydrogen; Alkyl residues (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, benzyl and 4-methylbenzyl, preferably 1 Substituted or unsubstituted, branched or straight chain alkyl moieties having from 7 to 7 carbon atoms); And aryl moieties (including substituted or unsubstituted aryl moieties such as phenyl, tolyl and xylyl groups).
Z may be a carbon atom to which three electron rich groups are bonded, such as a residue having the formula CG ¹ G ² G ³ . G ¹ , G ² and G ³ are the same or different, for example selected from the group consisting of OR ⁸ , SR ⁸ and NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are the same or different and are hydrogen; Alkyl residues (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, benzyl and 4-methylbenzyl, preferably 1 Substituted or unsubstituted, branched or straight chain alkyl moieties having from 7 to 7 carbon atoms); Or aryl moieties (including substituted or unsubstituted aryl moieties such as phenyl, tolyl and xylyl groups). Such Z includes triethoxymethyl or trimethoxymethyl.
Z may also be a heterocyclic moiety having the formula:
or
(Wherein
m is an integer from 1 to 6,
Q and Y are independently oxygen, sulfur or substituted or unsubstituted amines having the formula NR ⁵ . R ⁵ is hydrogen; Alkyl residues (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, benzyl and 4-methylbenzyl, preferably 1 Substituted or unsubstituted, branched or straight chain alkyl moieties having from 7 to 7 carbon atoms); Or aryl moieties (including substituted or unsubstituted aryl moieties such as phenyl, tolyl and xylyl groups). In the above formula, it should be understood that the two substituents R ⁶ and R ⁷ bonded to each methylene (ie CH ₂ group) of the moiety are selected independently of each other. Other, R ⁶ and R ⁷ groups on one methylene group is to be understood that such R ⁶ and R ⁷ groups on the other methylene, or may be different. Each R ⁶ and R ⁷ group is hydrogen; Alkyl residues (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, benzyl and 4-methylbenzyl, preferably 1 Substituted or unsubstituted, branched or straight chain alkyl moieties having from 7 to 7 carbon atoms); Aryl moieties (including substituted or unsubstituted aryl moieties such as phenyl, tolyl, xylyl, and naphthyl); Or a residue of formula OR ⁸ , SR ⁸ or NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are as defined above for the case where Z is formula CG ¹ G ² G ³ . Examples of preferred Z include isoxazoline moieties of the formula

(Wherein
R ⁶ , R ⁷ , R ¹² and R ¹³ are the same or different and are hydrogen; Alkyl residues (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, benzyl and 4-methylbenzyl, preferably 1 Substituted or unsubstituted, branched or straight chain alkyl moieties having from 7 to 7 carbon atoms); Aryl moieties (including substituted or unsubstituted aryl moieties such as phenyl, tolyl, xylyl, and naphthyl); Or a residue of formula OR ⁸ , SR ⁸ or NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are as defined above. m is 2 and it is preferable that R <^12> and R <^13> is hydrogen. More preferably, R ¹² and R ¹³ are hydrogen and R ⁶ and R ⁷ are each alkyl moieties having from 1 to 7 carbon atoms. Most preferred is that Z is 4,4-dimethylisoxazolin-2-yl, wherein R ¹² and R ¹³ are each hydrogen and R ⁶ and R ⁷ are methyl.
Several methods can be used to provide these regioisomers.
Method of Preparation of Regioisomer
In one embodiment of the invention, the regioisomer having the formula

Compounds having the formula below under conditions effective to produce

or

Α, α-disubstituted-methylbenzene derivatives having the formula

By acylating the regioisomer of the present invention.
In this embodiment, the acylating agent is a butyl derivative.
In another embodiment of the invention, the acylating agent is a 4- (α, α-disubstituted) -toluic acid derivative. In this embodiment, 4-( , -Disubstituted) -toluic acid derivative having the formula

Compounds having the formula below under conditions effective for acylation and

Get reacted.
X ¹ is halogen, whether a regioisomer is prepared using a method using a butyl derivative acylating agent or a regioisomer is prepared using a 4- (α, α-disubstituted) -toluic acid derivative acylating agent. Trialkyl or triaryl tin; Trialkyl or triaryl borate; Alkyl halo silicon; Trialkyl silicon; Or substituted sulfonic acid esters such as tosylate, mesylate or triflate, where the alkyl group is straight or branched and preferably has from 1 to 4 carbon atoms. Otherwise, X ¹ may be a useful substituent for organometallic coupling reactions, including lithium or magnesium compounds derived from bromine or iodine. As used herein, alkylhalosilicones represent tetravalent silicon atoms bonded to one or more halogens and one or more alkyl groups. The valence of the remaining silicon is bonded to the second halogen or the second alkyl. Particularly useful alkylhalo silicon has the formula -SiCH ₃ F ₂ .
In either case, X ² is hydrogen; halogen; Alkyl metal oxides; Residues having the formula -OR ¹⁰ ; Residues having the formula -SR ¹⁰ ; Or amines. Suitable amines are compounds having the formula -NR ¹⁰ R ¹¹ or -NR ¹⁰ (OR ¹¹ ); Cyclic amines having the formula:

or

Or heteroaryl amines such as imidazole, pyrazole and the like. R ¹⁰ and R ¹¹ are the same or different and are hydrogen; Alkyl residues (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, benzyl and 4-methylbenzyl, preferably 1 Substituted or unsubstituted, branched or straight chain alkyl moieties having from 7 to 7 carbon atoms); And aryl residues (including substituted or unsubstituted aryl residues such as phenyl, tolyl and xylyl groups); p is preferably 2 to 8 as an integer.
In carrying out the process using a butyl derivative acylating agent, suitable acylating agents include 4-substituted butanal or 4-substituted butyric acid derivatives. Examples of 4-substituted butyric acid derivatives are 4-substituted butyric acid halides, alkali metal 4-substituted butyric acid salts, 4-substituted butyric acid esters or 4-substituted butyric acid amides.
Suitable 4-substituted butyric acid halides include 4-substituted butyric acid fluorides, 4-substituted butyric chlorides and 4-substituted butyric acid bromide. When the alkali metal salt of 4-substituted butyric acid is used as the acylating agent, suitable alkali metals include lithium, sodium and potassium.
4-substituted butyric acid amides include N-unsubstituted amides such as 4-substituted butyric acid amides; N-monosubstituted amides such as N-methyl-4-substituted butyric acid amide, N-ethyl-4-substituted butyric acid amide, N-propyl-4-substituted butyric acid amide and N-hexyl-4-substituted butyric acid amide; Or N, N-disubstituted amides. Suitable N, N-disubstituted amides include N, N, -dimethyl-4-substituted butyric acid amide, N-methyl-N-ethyl-4-substituted butyric acid amide, N-methyl-N-propyl-4-substituted butyric acid amide, N -Methyl-N-hexyl-4-substituted butyric acid amide, N, N-diethyl-4-substituted butyric acid amide, N-ethyl-N-propyl-4-substituted butyric acid amide, N-ethyl-N-hexyl-4- Substituted butyric acid amides, N, N-dipropyl-4-substituted butyric acid amides, N-propyl-N-hexyl-4-substituted butyric acid amides and N, N-dihexyl-4-substituted butyric acid amides. N-methyl-N-methoxy-4-substituted butyric acid amide, N-methyl-N-ethoxy-4-substituted butyric acid amide, N-ethyl-N-methoxy-4-substituted butyric acid amide, and N-ethyl- Particularly useful are N, N-disubstituted butyric acid amides having the formula -NR ¹⁰ (OR ¹¹ ), such as N-ethoxy-4-substituted butyric acid amide. Suitable N, N-disubstituted amides are also cyclic amides such as butyric acid morpholine amide, butyric acid piperazine amide, butyric acid imidazole amide and butyric acid pyrazole amide and compounds of the formula

Wherein p is an integer, preferably 2 to 8, and examples thereof include N, N-ethylene-4-substituted butyric acid amide, N, N-propylene-4-substituted butyric acid amide, N, N Butylene-4-substituted butyric acid amide and N, N-pentylene-4-substituted butyric acid amide.
Whether the regioisomer is prepared using the method using a butyl derivative acylating agent or using the method using the 4- (α, α-disubstituted) -toluic acid derivative acylating agent, the acylation reaction is carried out in a suitable solvent. It is carried out for about 1 to 120 hours in the presence of a suitable catalyst at about -78 ℃ to reflux temperature of the solvent. Suitable solvents for acylation include hydrocarbon solvents such as benzene, toluene, xylene or cyclohexane; Halogenated hydrocarbons such as chlorobenzene, dichloroethane, methylene chloride, chloroform or carbon tetrachloride; Carbon disulfide; Dimethylformamide; Ethereal solvents such as tetrahydrofuran and diethyl ether; Or dioxane.
In carrying out the above methods, various catalysts can be used when A is hydrogen. Suitable catalysts include palladium chloride, palladium acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), or benzylchlorobis (triphenylphosphine) palladium (II) Such as palladium catalysts; Or nickel-phosphine catalysts. Acylation can also be carried out in the presence of added lithium chloride or triphenylphosphine. This second reaction is known in the art as an organometallic cross-linking reaction and di. D. Milstein et al., J. Org. Chem., 1979, 44, 1613 (“Milstein (1979)”); J. Org. Chem, et al. , 1983, 48, 4634 ("Labadie"); C. Sahlberg et al., Tetrahedron Letters, 1983, 24, 5137 ("Sahlberg"); D. Milstein et al., J. Am. In the general procedure of Chem. Soc., 1978, 100, 3636 ("Milstein (1978)") and K. Tamao et al. (Tetrahedron, 1982, 38, 3347 ("Tamao"). (All of which are incorporated herein by reference).
When acylation is carried out by a method using a butyl derivative acylating agent, when reacting with a methylbenzene derivative, it is also reacted by adding an acylation promoter which substitutes X ¹ from the bonded carbon to form a reactive carboanion salt. It can also promote. Suitable acylation promoters are butyl lithium, which is particularly effective when X ² is an amine. Preferred acylation promoters when X ² is chloride are magnesium metal or tetraalkyl tin. Acylation promoters, in particular organometals such as butyl lithium, are highly reactive with carbonyl groups. For this reason, the Z moiety is chosen to minimize the reactivity of the beta carbon to the benzene ring. Specifically, in the case of using an acylation promoter, a Z residue (for example, an isoxazolidium group) having the formula below is preferable.

Α, α-disubstituted-methylbenzene derivatives having the formula

Α, α-disubstituted-methylbenzene derivatives having the formula

It can be provided by reacting with a methylating agent under conditions effective to produce an α, α-disubstituted-methylbenzene derivative. The methylation reaction is carried out at a temperature of about −78 ° C. to room temperature in a suitable solvent, potassium t-butoxide, sodium hydride, lithium diisopropylamide (“LDA”), lithium hexamethyldisilazide (“LHMDS”), potassium hexa It is carried out for about 1 to about 120 hours in the presence of a suitable non-nucleophilic base or related strong base such as methyldisilazide (“KHMDS”), sodium or lithium tetramethylpiperidine. The reaction is preferably carried out in an inert, dry atmosphere such as N ₂ or Ar gas in an inert, dry solvent. Suitable solvents for methylation include hydrocarbon solvents such as benzene, toluene, xylene or cyclohexane; Halogenated hydrocarbons such as chlorobenzene, dichloroethane, methylene chloride or carbon tetrachloride; Carbon disulfide; Dimethylformamide; Ethereal solvents such as tetrahydrofuran, t-butyl methyl ether and diethyl ether; Or dioxane. At least 2 molar equivalents, preferably 2.1 to 3 molar equivalents of methylating agent, are added during the reaction either continuously or in two or more chunks. Suitable methylating agents include iodomethane, bromomethane, chloromethane, dimethylsulfate and the like.
Α, α-disubstituted-methylbenzene derivative having the formula

Corresponding α, α-disubstituted benzyl acids of the formula

Suitable aminoalkyl derivatives having the general formula
H ₂ N- (CR ⁶ R ⁷ ) _m -QH
It can be prepared by reacting under conditions effective to produce α, α-disubstituted methylbenzene derivatives. This reaction is carried out for about 1 to about 120 hours in the range of 0 ° C. to the reflux temperature of the solvent in a suitable solvent. Suitable solvents for this reaction include hydrocarbons such as benzene, toluene, xylene or cyclohexane; Halogenated hydrocarbons such as chlorobenzene, dichloroethane, methylene chloride, chloroform or carbon tetrachloride; Carbon disulfide; Dimethylformamide; Ethereal solvents such as tetrahydrofuran and diethyl ether; Or dioxane. The solvent is preferably kept at reflux in a device having means for removing water, such as a Dean-Stark trap. In many cases, it is advantageous to convert the α, α-disubstituted-benzyl acid derivatives to the corresponding acid halides by treating with thionyl chloride prior to the reaction of the aminoalkyl derivatization.
Alternatively, α, α-disubstituted-methylbenzene derivatives having the formula

Α, α-disubstituted-benzyl acid derivatives having the formula:

The aminoalkyl derivatives can be prepared by reacting under the conditions described above for the α, α-disubstituted-benzyl acid conversion.
The α, α-disubstituted-benzyl acid derivatives used to prepare the α, α-disubstituted-methylbenzene derivatives can be synthesized by methylating the corresponding α, α-disubstituted-benzyl acid derivatives. Conditions suitable for carrying out this methylation are as described above for the methylation of α, α-bisubstituted-methylbenzene derivatives.
4- (α, α-disubstituted) -toluic acid derivatives having the formula

When performing acylation using this 4- (α, α-disubstituted) -toluic acid derivative, 4- (α, α-disubstituted) -toluic acid derivative having the formula

It can be obtained by reaction with a methylating agent under conditions effective to produce 4- (α, α-disubstituted) -toluic acid derivatives. Suitable methylation conditions are as described above. 4- (α, α-ibsubstituted) -toluic acid derivatives having the formula

The corresponding 4- (α-carboxy-α, α-ibsubstituted) -toluic acid derivatives having the formula:

With suitable aminoalkyl derivatives having the formula below under conditions effective to produce 4- (α, α-ibsubstituted) -toluic acid derivatives;
H ₂ N- (CR ⁶ R ⁷ ) _m -QH
It can be prepared by reacting with. Conditions suitable for carrying out this reaction are as described above for the reaction of α, α-bisubstituted-methylbenzene derivatives with aminoalkyl derivatives.
Alternatively, 4- (α, α-disubstituted) -toluic acid derivatives having the formula

4- (α-carboxy-α, α-disubstituted) -toluic acid derivatives having the formula:

The aminoalkyl derivative can be prepared by reacting the α, α-bisubstituted-benzyl acid derivative with the aminoalkyl derivative under the conditions described above.
The 4- (α-carboxy-α, α-disubstituted) -toluic acid derivatives used to prepare 4- (α, α-disubstituted) -toluic acid derivatives have the corresponding 4- (α-carboxy-α, α- Unsubstituted) -toluic acid derivatives can be synthesized by methylation. Conditions suitable for carrying out this methylation are as described above for the methylation of α, α-bisubstituted-methylbenzene derivatives.
Regioisomers of the present invention having the formula

Methylation using the reagents and conditions described above for the methylation of α, α-disubstituted-methylbenzene derivatives can be made from the corresponding α, α-disubstituted regioisomeric precursors having the formula:

In the case of using this pathway, the α, α-disubstituted regioisomer precursor is used to convert α, α-disubstituted-methylbenzene derivatives having the formula

Acylating agents having the formula

or

It is convenient to prepare by acylation under conditions effective to produce α, α-disubstituted regioisomer precursors. Suitable acylation conditions for this reaction are as described above for the acylation of α, α-disubstituted-methylbenzene derivatives.
Alternatively, α, α-disubstituted regioisomer precursors are combined with 4- (α, α-disubstituted) -toluic acid derivatives having the formula:

Compound having the formula

It can be prepared by reacting under conditions effective to produce α, α-disubstituted regioisomer precursors. This reaction can be carried out under the same reaction conditions as described above for the acylation of α, α-disubstituted-methylbenzene derivatives.
Method for Converting Regioisomers to Piperidine Derivatives with Keto Groups
Once the regioisomer is obtained, it is converted to the piperidine derivative using the piperidine compound.
In one aspect of the invention, the regioisomer is a first intermediate compound having the formula

It can be hydrolyzed under conditions effective to form. The regioisomer is converted to the first intermediate compound upon treatment with an inorganic acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid. The hydrolysis reaction is carried out for about 0.5 to 24 hours in the presence of a catalytic amount of base, optionally at -40 ° C to the reflux temperature of the solvent in a suitable solvent. Suitable solvents for the hydrolysis reaction include hydrocarbon solvents such as benzene, toluene, xylene or cyclohexane; Ethereal solvents such as ether, tetrahydrofuran dioxane or dimethoxyethane; Or halogenated hydrocarbons such as chlorobenzene, methylene chloride, carbon tetrachloride, chloroform or dichloroethane.
If desired, the acid groups of the first intermediate compound are evaporated to an alcoholic solution of an acid and an inorganic acid, such as a methanol, ethanol, propanol or butanol solution of hydrochloric acid, hydrobromic acid or hydroiodic acid, until drying to give an ester having the formula

As can be formed, it can be esterified by techniques known to those skilled in the art.
After hydrolysis and optional esterification, the first intermediate compound or ester thereof is a piperidine derivative having a keto group of the formula

Under conditions effective to form a piperidine compound of the formula

Can react. This alkylation reaction is carried out in a suitable solvent at about 70 ° C. to the reflux temperature of the solvent, preferably in the presence of a base and optionally in the presence of a catalytic amount of potassium iodide for about 4 to 120 hours. Suitable solvents for the alkylation reaction include alcohol solvents such as methanol, ethanol, isopropyl alcohol or n-butanol; Ketone solvents such as methyl isobutyl ketone or methyl ethyl ketone; Hydrocarbon solvents such as benzene, toluene or xylene; Halogenated hydrocarbons such as chlorobenzene or methylene chloride; Or dimethylformamide. Suitable bases for the alkylation reaction include, for example, inorganic bases such as sodium bicarbonate, potassium carbonate or potassium bicarbonate or organic bases such as trialkylamines such as triethylamine or pyridine, or excess piperidine Compounds can be used. If the piperidine derivative is in the form of an ester, it can be hydrolyzed to carboxylic acid.
Piperidine derivative compounds of the invention wherein n is 1 can also be prepared by the following other alkylation procedures. After hydrolysis and optional esterification, the first intermediate compound having the formula

4- in the presence of an acid binding reagent such as alkali metal carbonate or bicarbonate at a temperature of 80 ° C. to 140 ° C. in an organic solvent such as toluene, dioxane, xylene, methyl isobutyl ketone, methyl ethyl ketone or N, N-dimethylformamide Reaction with hydroxypiperidine forms an N-substituted hydroxypiperidine having the formula

This N-substituted hydroxypiperidine is then substituted with diphenylmonohamethane having the formula

(Wherein X ⁴ is halogen)
The reaction is carried out under conditions effective to form a piperidine derivative of the formula

The reaction is carried out in an inert organic solvent such as toluene, xylene, dioxane, methyl isobutyl ketone, methyl ethyl ketone or N, N-dimethylformamide, an acid such as alkali metal carbonate or bicarbonate at a temperature of 80 ° C. to 140 ° C. -Preferably in the presence of binding reagents. Diphenylmonohamethane is commercially available or is known in the art, for example, by reacting the corresponding diphenylmethanol with phosphorus chloride or thionyl chloride or phosphorus bromide or thionyl bromide in an inert organic solvent. It can manufacture by a well-known method. This alternative alkylation method is preferred when R ³ in the first intermediate compound is -COOH.
Regardless of the alkylation procedure used, when R ³ is —COOalkyl, basic hydrolysis may be carried out after the alkylation reaction to convert substituent-COOalkyl groups of R ³ to the —COOH group. This basic hydrolysis process treats the piperidine derivative with an inorganic base such as sodium hydroxide for about 1/2 to 12 hours at reflux in an aqueous lower alcohol solvent such as aqueous methanol, ethanol, isopropyl alcohol or n-butanol. It involves doing.
Piperidine compounds where n = 0 and R ¹ and R ² are each hydrogen or n = 0, R ¹ is hydroxy and R ² is hydrogen are commercially available, or in the art It may be prepared according to well known procedures (eg, FJ McCarty, CH Tilford, MG Van Campen, J. Am. Chem. Soc., 1961, 26, 4084 (incorporated herein by reference). Piperidine compounds when n = 0 and R ¹ and R ² form a second bond between the carbon atoms containing R ¹ and R ² are selected from the corresponding compounds in which R ¹ is hydroxy It may be prepared by dehydration by a procedure generally known in the art. When n = 1 and R ¹ and R ² are both hydrogen, the piperidine compound is suitably substituted diphenylmonohalo such as diphenylchloromethane, diphenylbromomethane and di (p-tolyl) chloromethane Methane and 1-alkoxycarbonyl-4-hydroxypiperidine are prepared by condensation in a suitable solvent such as toluene, xylene, dioxane, methyl isobutylketone, methyl ethyl ketone or N, N-dimethylformamide. This reaction is carried out in the presence of a base such as an alkali metal carbonate or bicarbonate at a temperature of 80 ° C to 140 ° C. After this reaction, hydrolysis at the boiling point of the solvent with an alkali metal hydroxide in an organic solvent such as ethanol or isopropanol yields 4- (diarylmethoxy) -piperidine free base.
In another aspect of the present invention, the piperidine derivative compound is a regioisomer having the formula

Using a piperidine compound having the following formula under conditions effective to form a piperidine derivative precursor

Produced by conversion to a piperidine derivative precursor having the formula

This alkylation reaction is preferably carried out in the presence of a base and optionally in the presence of a catalytic amount of potassium iodide at about 70 ° C. to the reflux temperature of the solvent for about 4 to 120 hours. Suitable solvents for the alkylation reaction include alcohol solvents such as methanol, ethanol, isopropyl alcohol or n-butanol; Ketone solvents such as methyl isobutyl ketone and methyl ethyl ketone; Hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as chlorobenzene or methylene chloride; Or dimethylformamide. Suitable bases for the alkylation reaction include inorganic bases such as sodium bicarbonate, potassium carbonate or potassium bicarbonate, or organic bases such as trialkylamines, for example triethylamine or pyridine, or excess use of piperidine compounds have.
Alternatively, the piperidine derivative precursor of the present invention, wherein n is 1, is combined with the regioisomer having the formula

4-hydroxypiperidine is reacted with alkali metal carbonates or bicarbonates at temperatures between 80 ° C. and 140 ° C. in organic solvents such as toluene, dioxane, xylene, methyl isobutyl ketone, methyl ethyl ketone or N, N-dimethylformamide. It can be prepared by reacting in the presence of an acid-binder to form N-substituted hydroxypiperidine having the formula

This N-substituted hydroxypiperidine is then under conditions effective to form a piperidine derivative precursor of the formula

Diphenyl monohalo methane having the formula

(Wherein X ⁴ is halogen). The reaction is in the presence of an acid-binder such as an alkali metal carbonate or bicarbonate at a temperature of 80 ° C. to 140 ° C. in an inert organic solvent such as toluene, xylene, dioxane, methyl isobutyl ketone, methyl ethyl ketone or N, N-dimethylformamide. It is preferable to carry out under.
According to another aspect of the present invention, a piperidine derivative having a keto group is prepared from an α, α-disubstituted-methylbenzene derivative having the following formula.

In this production method, the α, α-disubstituted-methylbenzene derivative is converted to a piperidine compound, preferably 4- (4-substituted-piperidin-1-yl) butanal or 4- (4-substituted-piperi) A din-1-yl) butyric acid derivative compound is used to convert to a piperidine derivative precursor having the formula

4- (4-substituted-piperidin-1-yl) butanal and 4- (4-substituted-piperidin-1-yl) butyric acid derivative compounds suitable for use in this acylation reaction are compounds having the formula Wherein X ² in the formula is as defined above.

This conversion is carried out in a suitable solvent for about 1 to 120 hours in the presence of a suitable catalyst at about -78 ℃ to the reflux temperature of the solvent. Suitable solvents for this acylation include hydrocarbon solvents such as benzene, toluene, xylene or cyclohexane; Halogenated hydrocarbons such as chlorobenzene, dichloroethane, methylene chloride, chloroform or carbon tetrachloride; Carbon disulfide; Dimethylformamide; Ethereal solvents such as tetrahydrofuran and diethyl ether; Or dioxane.
When A is hydrogen, various catalysts can be used. Suitable catalysts include palladium chloride, palladium acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), or benzylchlorobis (triphenylphosphine) palladium (II) Such as palladium catalysts; Or nickel-phosphine catalysts. The acylation reaction can also be carried out in the presence of added lithium chloride or triphenylphosphine. The cross-linking reaction is carried out by the general procedure of Milstein (1979), Labadi, Salberg, Milstein (1978) and Tamao (all of which are incorporated herein by reference).
The acylation reaction may also be promoted by addition of an acylation promoter which, when reacted with the methylbenzene derivative, substitutes for X ¹ from the benzene ring to form a reactive carboanion salt. Suitable acylation promoters are butyl lithium, which is particularly effective when X ² is an amine. Preferred acylation promoters when X ² is chloride are magnesium metal or tetraalkyl tin.
Other suitable 4- (4-substituted-piperidin-1-yl) butanal and 4- (4-substituted-piperidin-1-yl) butyric acid derivatives have 4- (4-hydroxy- Piperidin-1-yl) butanal and 4- (4-hydroxy-piperidin-1-yl) butyric acid derivatives.

In this method useful for preparing a piperidine derivative precursor in which n is 1, the α, α-disubstituted-methylbenzene derivative is a N-substituted hydroxypiperidine having the formula

It is converted using 4- (4-hydroxy-piperidin-1-yl) butyric acid derivative under conditions effective to produce The N-substituted hydroxypiperidine is then converted to the piperidine derivative precursor using diphenylmonohamethane as described above.
Alternatively, N-substituted hydroxypiperidine may be substituted with an N-substituted piperidine compound having the formula

It can be hydrolyzed under conditions effective to produce. Suitable hydrolysis conditions are as described below with respect to the hydrolysis of the piperidine derivative precursor. The hydrolyzed N-substituted piperidine compounds can then be converted to piperidine derivatives using diphenylmonohamethane as described above.
In another aspect of the present invention, piperidine derivatives having keto groups are prepared from 4- (α, α-disubstituted) -toluic acid derivatives having the formula:

In this production method, 4- (α, α-disubstituted) -toluic acid derivatives have the following formula

A piperidine compound such as (wherein X ¹ is as defined above), preferably 3- (4-substituted-piperidin-1-yl) propane, to a piperidine derivative precursor having the formula Switch.

This conversion is carried out in a suitable solvent at about 78 ° C. to the reflux temperature of the solvent in the presence of a suitable catalyst for about 1 to 120 hours. Suitable solvents and catalysts are as described above in connection with converting α, α-disubstituted-methylbenzene derivatives to piperidine derivative precursors.
Other suitable 3- (4-substituted-piperidin-1-yl) propane derivatives include 3- (4-hydroxy-piperidin-1-yl) propane derivatives having the formula:

In this method useful for preparing piperidine derivative precursors with n equal to 1, 4- (α, α-disubstituted) -toluic acid derivatives are subjected to conditions effective to produce N-substituted hydroxypiperidine having the formula

It is converted using 3- (4-hydroxy-piperidin-1-yl) propane derivative. Then, the N-substituted hydroxypiperidine compound of the N-substituted piperidine compound having the formula

Diphenylmonohamethane is used to convert the piperidine derivative precursor either before or after hydrolysis for conversion.
Then, regardless of the alkylation procedure used, the piperidine derivative precursor is converted to a piperidine derivative compound having the formula:

This conversion can be effected by treating the piperidine derivative precursor with an inorganic acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid at about -40 ° C. to about reflux temperature of the solvent in a suitable organic solvent. Suitable solvents include alcohols such as methanol, ethanol, isopropanol and various glycols; Hydrocarbon solvents such as benzene, toluene, xylene or cyclohexane; Ethereal solvents such as ether, tetrahydrofuran, dioxane or dimethoxyethane; Or halogenated hydrocarbons such as chlorobenzene, methylene chloride, carbon tetrachloride, chloroform or dichloroethane. Alternatively, this conversion can proceed in vivo by administering the piperidine derivative to the subject and allowing the subject to metabolize the piperidine derivative precursor to the piperidine derivative compound. Dosage and form are as discussed above for the administration of the piperidine derivative compounds of the present invention.
Reduction of keto groups in piperidine derivatives and piperidine derivative precursors
As discussed above, the method of the present invention is useful for preparing piperidine derivatives having keto or hydroxyl groups. Derivatives having keto groups can be converted to analogous compounds having hydroxyl groups by reduction reactions well known in the art.
Reduction can be carried out using sodium borohydride or potassium borohydride in a lower alcohol solvent such as methanol, ethanol, isopropyl alcohol or n-butanol.
When lithium aluminum hydride or diborane is used as the reducing agent, suitable solvents are, for example, diethyl ether, tetrahydrofuran or dioxane. These reduction reactions are carried out at about 0 ° C. to the reflux temperature of the solvent, and the reaction time is in the range of about 0.5 to 8 hours.
In lower alcohol solvents such as methanol, ethanol, isopropyl alcohol or n-butanol or acetic acid or mixtures of aqueous solutions thereof, for example, Raney nickel, palladium, platinum or rhodium catalysts are used with hydrogen or in isopropyl alcohol Catalytic reduction using propoxide can also be used. Reduction using sodium borohydride is generally preferred for catalytic reduction when forming carboxylic acids or esters.
The piperidine derivatives containing hydroxy groups thus prepared can optionally be separated into their pure enantiomeric components by conventional methods. For example, racemic mixtures of piperidine derivative enantiomers can be converted to racemic mixtures of diastereomers using reactive chiral agents. The diastereomer is then separated, for example by recrystallization or chromatography, and the reactive chiral agent is cleaved to recover the pure enantiomer. Alternatively, the racemic mixture of piperidine derivative enantiomers can be separated by chromatographic separation using a chiral stationary phase or by recrystallization using a chiral solvent.
Piperidine derivatives with keto groups can also be converted to pure enantiomers of piperidine derivatives with hydroxy groups using chiral reducing agents. For example, reduction with (+)-B-chlorodiisopropinocampphenyl-borane yields piperidine derivatives having R chirality to the carbon to which the hydroxy group is bound. Alternatively (-)-B-chlorodiisopropinocampphenyl borane is used to generate S enantiomers. Other suitable chiral reducing agents are (R) and (S) oxazaborolidin / BH ₃ , potassium 9-O- (1,2: 5,6-di-O-isopropylidine-α-D-glucofuransoyl) -9-voratabicyclo [3.3.1] nonane, (R) and (S) -B-3-pinanyl-9-borabicyclo [3.3.1] nonane, NB-enanthtride, lithium (R) -(+) And (S)-(-)-2,2'-dihydroxy-1,1'-binafthyl alkoxy aluminum hydride, (R)-(+) and (S)-(-) -2,2'-dihydroxy-6,6'-dimethylbiphenyl borane-amine complex, tris (((1S, 2S, 5R) -2-isopropy-5-methyl-cyclohex-1-yl) Methyl) aluminum, ((((1R, 3R) -2,2-dimethylbicyclo [2.2.1] hept-3-yl) methyl) beryllium chloride, (R) -BINAP-ruthenium complex / H ₂ , and 6, 6'-bis (diphenylphosphino) -3,3'-dimethoxy-2,2 ', 4,4'-tetramethyl-1,1'-biphenyl.
Once esters having hydroxyl groups are formed, carboxylic acids can be obtained using basic hydrolysis. Such procedures are well known and generally involve treatment with an inorganic base such as sodium hydroxide or potassium hydroxide in an aqueous lower alcohol solvent such as aqueous methanol, ethanol, isopropyl alcohol or n-butanol. Basic hydrolysis is carried out at about room temperature to the reflux temperature of the solvent for about 1/2 hour to 12 hours.
In a similar manner, piperidine derivative precursors containing keto groups having the formula

It can be reduced to a piperidine derivative precursor containing a hydroxyl group having the formula:

The piperidine derivative precursor containing a hydroxyl group may be treated with a strong acid as described above (ex vivo) or by administering a piperidine derivative precursor containing a hydroxyl group (in vivo) to a subject having the formula Ferridine derivative

Can be converted to
The invention will be further illustrated by the following examples.
Example 1 Preparation of 4-bromo-α- (4,4-dimethylisoxazolin-2-yl) toluene
A mixture of 4-bromophenylacetic acid (172 g, 0.800 mol), 2-amino-2-methyl-1-propanol (115 ml, 1.20 mol) and 900 ml xylene for 24 hours in a device equipped with a Dean-Stark trap It was refluxed. The mixture was then cooled, filtered and concentrated to give a crystalline solid. This solid was slurried in hexane to give 147 g of a white solid. The hexane filtrate was then concentrated, slurried with hexane and filtered to give 13 g of 4-bromo-α- (4,4-dimethylisoxazolin-2-yl) toluene as a white solid. All together yielded 160 g (75%).
Example 2 Preparation of 4-Bromo-α, α-dimethyl-α- (4,4-dimethylisoxazolin-2-yl) toluene
A 250 ml three necked round bottom flask was prepared under N _{2 with} 5.0 g (0.0186 mol) of 4-bromo-α- (4,4-dimethylisoxazolin-2-yl) toluene prepared according to Example 1 and dried THF 50 Filled with ml. Then 27 ml (0.0279 moles, 1.5 equiv) of KHMDS were added slowly over 10 minutes. It was observed that the color changed to a dark orange color. The mixture was stirred for 15 minutes at room temperature, then 1.16 mL (0.0186 mol, 1 equiv) of methyl methyl iodide was added in one portion. The reaction exothermed to 46 ° C. and a white solid precipitated while the solution was pale yellowish. After stirring for 1 hour, 27 mL (0.0279 mol, 1.5 equiv) of KHMDS was added to raise the reaction temperature from 27 ° C. to 30 ° C. and the color changed to orange. After the reaction was stirred for a further 20 minutes, a second equivalent of CH ₃ I was added. An amount was removed, quenched with water and extracted with ethyl acetate. TLC analysis (4: 1 hexanes / ethyl acetate) showed the more polar 4-bromo-α-methyl-α (4,4-dimethylisoxazolin-2-yl) toluene (“single adduct”) Appeared to be. Adding an additional 0.2 ml of CH ₃ I changed the pale yellow solution to white. The reaction mixture was then added with 100 mL 10% acetic acid / water with 250 mL methylene chloride. The organic layer was washed twice with 50 ml brine and dried over sodium sulfate. After concentration and drying at room temperature and 0.1 mm Hg pressure overnight, 5.65 g (103%) of a yellow solid was obtained. This solid was dissolved in 30 ml of isopropanol and 20 ml of water was slowly added until an oil formed. 5 ml of isopropanol was added to the mixture while heating to dissolve all oils. Cooling in an ice bath, the oil recrystallizes and 4.61 g (0.0156) of pure 4-bromo-α, α-dimethyl-α- (4,4-dimethylisoxazolin-2-yl) toluene free of any single adduct Mmol, 84%).
Example 3 4- (4-Chloro-1-oxobutyl) -α, α-dimethyl-α- (4,4-dimethylisoxazolin-2-yl) toluene
A solution of 4-bromo-α, α-dimethyl-α- (4,4-dimethylisoxazolin-2-yl) toluene (10.0 g, 0.0338 mol) prepared in accordance with Example 2 in 400 mL THF- Cool to 78 ° C., n-butyllithium (16. mL, 0.042 mol) is added via syringe and the mixture is stirred at −78 ° C. for 30 minutes. While maintaining the temperature below −75 ° C., 4-chlorobutyryl chloride (14.4 g, 0.102 mol) in 30 mL of THF is added dropwise and the mixture is stirred at −78 ° C. for 30 minutes. The mixture is warmed to -15 ° C and quenched with water. The product is extracted with methylene chloride, washed with saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated. The residue is cooled to 0 ° C., treated with minimal acetonitrile and filtered to give 4- (4-chloro-1-oxobutyl) -α, α-dimethyl-α- (4,4-dimethylisoxazolin 2-yl) toluene is obtained.
Example 4 Preparation of 4- (4-chloro-1-oxobutyl) -α, α-dimethylphenylacetic acid
4- (4-Chloro-1-oxobutyl) -α, α-dimethyl-α- (4,4-dimethylisoxazolin-2-yl) toluene (47.8 g, 0.15 mol) prepared according to Example 3 A mixture of 150 mL concentrated hydrochloric acid and 150 mL 1,4-dioxane is refluxed for 18 hours. The mixture is extracted three times with ethyl acetate. The organics are washed with saturated NaCl solution, dried over MgSO ₄ and concentrated. The crude product is purified by column chromatography using silica gel, eluting with hexane / ethyl acetate / acetic acid. The cleaner fractions are combined and recrystallized from methylene chloride / hexane to give 4- (4-chloro-1-oxobutyl) -α, α-dimethylphenylacetic acid.
Example 5 Preparation of Methyl 4- (4-Chloro-1-oxobutyl) -α, α-Dimethylphenyl Acetate
A solution of 4- (4-chloro-1-oxobutyl) -α, α-dimethylphenylacetic acid, prepared according to example 4 in 450 ml of HCl-saturated methanol, was refluxed for 1 hour. The mixture is concentrated to dryness and partitioned between ethyl acetate and water. The aqueous phase is extracted again with ethyl acetate twice. The combined organic phases are dried over MgSO ₄ and concentrated to an oil. The oil is purified by column chromatography using silica gel, eluting with hexane / ethyl acetate. The clean fractions are combined and concentrated to give methyl 4- (4-chloro-1-oxobutyl) -α, α-dimethylphenylacetate.
Example 6 Preparation of Methyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-oxobutyl] -α, α-dimethylphenylacetate
A solution of 12.6 g of methyl 4- (4-chloro-1-oxobutyl) -α, α-dimethylphenylacetate, prepared according to Example 5 in 500 mL of toluene in a 1 L three-neck flask, was mechanically stirred with 4- ( 8.8 g of α, α-diphenyl) piperidinemethanol) and 23 g of K ₂ CO ₃ , and the mixture is refluxed for 7 hours. The cooled reaction mixture is then filtered and concentrated in vacuo. The residue is dissolved in Et ₂ O and treated with excess etheric HCl. The mixture is then concentrated to a solid state. The solid is treated with EtOAc and collected by filtration. The product is then partitioned between EtOAc and 2N Na ₂ CO ₃ . The organics were dried over MgSO ₄ , filtered and concentrated in vacuo to afford methyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-oxobutyl] -α, α- Dimethylphenyl acetate was obtained.
Example 7 Preparation of Methyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylphenylacetate
Methyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-oxobutyl] -α, α-dimethylphenylacetate prepared according to Example 6 in 250 mL of CH ₃ OH. 13.5 g of the solution was cooled in an ice CH ₃ OH bath and 1.8 g of NaBH ₄ were added in portions. After 1 hour, the mixture is concentrated to a solid. The residue is partitioned between EtOAc and saturated aqueous NaHCO ₃ solution. The aqueous portion is extracted with EtOAc. The combined organics were washed with saturated aqueous NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo to methyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1 with foam. -Hydroxybutyl] -α, α-dimethylphenylacetate is obtained.
Example 8 Preparation of 4- [4- [4-hydroxydiphenylmethyl] -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylphenylacetic acid
Methyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -prepared according to example 7 in 300 ml CH ₃ OH and 150 ml H ₂ O. 10 g of NaOH is added to a solution of 9.5 g of α, α-dimethylphenylacetate. The mixture is refluxed for 1 hour and then cooled. CH ₃ OH is removed in vacuo. The concentrate is diluted with H ₂ O and CHCl ₃ and the pH is adjusted to approximately 5.5-6.0. The phases are separated and the aqueous phase is extracted with CHCl ₃ . The combined organics are dried over MgSO ₄ , filtered and stripped to give the crude product.
The crude product was dissolved in _{CH 2 Cl 2, CHCl 3,} CHCl 3 10% in CH ₃ OH, CHCl ₃ is by varying a 25% CH ₃ OH eluted in the non real-grade (Davisil Grade) 633 SiO ₂ phase chromatography do. The product containing fractions are concentrated to give 4- [4- [4-hydroxydiphenylmethyl] -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylphenylacetic acid.
Example 9 Preparation of Methyl 4- [4- [4- (bis (4-methylphenyl) hydroxymethyl) -1-piperidinyl] -1-oxobutyl] -α, α-dimethylphenylacetate
To a solution of 6.4 g (0.017 mol) of methyl 4- (4-chloro-1-oxobutyl) -α, α-dimethylphenylacetate prepared according to Example 5 in 500 mL of toluene in a 1 liter round bottom flask equipped with a mechanical stirrer 5.1 g (0.017 mol) of 4- (α, α-bis (4-methylphenyl) -piperidinemethanol are added followed by 11.8 g (0.086 mol) of solid potassium carbonate The solution is heated to reflux for 24 hours After cooling, the mixture is filtered and toluene is removed in vacuo The residue is partitioned between ethyl acetate and 2N sodium carbonate solution The aqueous layer is extracted twice with ethyl acetate and the combined organic layers are dried over sodium sulfate and acetic acid Ethyl is removed in vacuo to afford methyl 4- [4- [4- (bis (4-methylphenyl) hydroxymethyl) -1-piperidinyl] -1-oxobutyl] -α, α-dimethylphenylacetate.
Example 10 Preparation of Methyl 4- [4- [4- (bis (4-methylphenyl) hydroxymethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylphenylacetate
Methyl 4- [4- [4- (bis (4-methylphenyl) hydroxymethyl) -1-piperidinyl] -1 prepared according to Example 9 in 150 ml of methanol in a 500 ml round bottom flask equipped with a mechanical stirrer. 0.86 g (0.023 mol) of sodium borohydride are slowly added to a 6.8 g (0.013 mol) -10 ° C. solution of -oxobutyl] -α, α-dimethylphenylacetate, and the reaction is stirred for 2 hours. Methanol is removed in vacuo and the residue is partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous layer is extracted with ethyl acetate, the combined organic layers are dried over sodium sulfate, and ethyl acetate is removed in vacuo to give a crude product. The resulting material was eluted by column chromatography (Davisil Grade 633 silica gel packed in methylene chloride, the material was placed in chloroform, eluting with 2% methanol for methylene chloride to 5% methanol for methylene chloride). Purification gives methyl 4- [4- [4- (bis (4-methylphenyl) hydroxymethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylphenylacetate.
Example 11 Preparation of 4- [4- [4- (bis (4-methylphenyl) hydroxymethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylphenylacetic acid
Methyl 4- [4- [4- (bis (4-methylphenyl) hydroxymethyl) -1-piperidinyl] -1 prepared according to Example 10 in 350 ml of methanol in a 1 l round bottom flask equipped with a mechanical stirrer. -Hydroxybutyl] -α, α-dimethylphenylacetate 5.3 g (9.8 mmol), 5.1 g (0.13 mol) of solid sodium hydroxide and 100 mL of water are added. The mixture is heated to reflux for 3 hours. After cooling, methanol is removed in vacuo and 6N hydrochloric acid is added dropwise until the solution is no longer basic (pH = 7). The solution is extracted three times with ethyl acetate. Combine the organic layers and cause precipitation. The solid was washed with ether to dihydrate 4- [4- [4- (bis (4-methylphenyl) hydroxymethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylphenylacetic acid. Get into.
Example 12 Preparation of 4- (1-hydroxy-4-chlorobutyl) -α, α-dimethylphenylacetic acid
NaBH ₄ is added to a solution of 50 mg of 4- (4-chloro-1-oxobutyl) -α, α-dimethylphenylacetic acid prepared according to Example 4 in 3 ml of methanol. The mixture is stirred for 30 minutes, acidified with 2N HCl and methanol is removed in vacuo. The concentrate is extracted with EtOAc. The organics are dried over Na ₂ SO ₄ , filtered and concentrated to give 4- (1-hydroxy-4-chlorobutyl) -α, α-dimethylphenylacetic acid.
Example 13 Preparation of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-oxobutyl] -α, α-dimethylphenylacetic acid
800 mg of 4- (4-chloro-1-oxobutyl) -α, α-dimethylphenylacetic acid, 800 (4- (α, α-diphenyl) piperidinemethanol prepared according to Example 4 in 25 ml of toluene And 2.4 g of K ₂ CO ₃ are stirred at room temperature for 48 hours. The mixture is concentrated in vacuo. The residue is treated with EtOAc, filtered and concentrated to give 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-oxobutyl] -α, α-dimethylphenylacetic acid .
Example 14 Preparation of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylphenylacetic acid
4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-oxobutyl] -α, α-dimethylphenylacetic acid prepared according to Example 13 in 25 mL of CH ₃ OH and A mixture of 300 mg NaBH ₄ is stirred overnight at room temperature. The mixture is then concentrated in vacuo. The residue is partitioned between EtOAc and H ₂ O. The aqueous portion is treated with concentrated HCl to pH 6 and then extracted with EtOAc. The organics are concentrated in vacuo. The residue is dissolved in EtOAc, filtered and concentrated in vacuo to oil. This oil is dissolved in CH ₃ OH and concentrated to a solid. The solid was slurried with EtOAc, filtered and rinsed with EtOAc 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylphenyl Acetic acid is obtained.
Example 15-4- (4-Chloro-1-oxobutyl) -α, α-dimethyl-α- (4,4-dimethylisoxazolin-2-yl) toluene
Magnesium (96 mg, 3 mM) was suspended in tetrahydrofuran. Small iodine crystals were added to activate magnesium. Solid 4-bromo-α, α-dimethyl-α- (4,4-dimethylisoxazolin-2-yl) toluene (600 mg, 2 mM) prepared according to Example 2 was added and the mixture was allowed to room temperature After stirring for 6 hours, it is refluxed for 6 hours and then cooled to room temperature. After addition of 4-chlorobutyronitrile, the mixture is stirred overnight and then poured into cold dilute acid. The acid solution is extracted with ethyl acetate, the organic layer is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to give an almost colorless oil in 93% yield. Spectral analysis is consistent with 4- (4-chloro-1-oxobutyl) -α, α-dimethyl-α- (4,4-dimethylisoxazolin-2-yl) toluene.
Example 16 Preparation of 4-formyl-α, α-dimethyl-α- (4,4-dimethylisoxazolin-2-yl) toluene
4-Bromo-α, α-dimethyl-α- (4,4-dimethylisoxazolin-2-yl) toluene (1 g, 3.4 mM) prepared according to Example 2 was -78 in a dry ice bath. Cool to C and add 2 M butyllithium solution (3.4 mM). The mixture was stirred for 15 minutes, 2 mL of DMF was added, the dry ice bath was removed and the mixture was warmed to 0 ° C. The 0 ° C. solution was poured into cold brine and extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate. The solvent was removed under reduced pressure to obtain a white solid whose proton NMR spectrum was consistent with 4-formyl-α, α-dimethyl-α- (4,4-dimethylisoxazolin-2-yl) toluene.
While the invention has been described in detail for purposes of illustration, these details are for purposes of illustration only, and those skilled in the art will understand that various modifications may be made without departing from the spirit and scope of the invention as defined in the following claims.

权利要求:
Claims (71)
[1" claim-type="Currently amended] Providing a regioisomer having the formula:

(Wherein
Z is -CG ¹ G ² G ³ ,
or ego;
m is an integer from 1 to 6;
Q and Y are the same or different and are selected from the group consisting of O, S and NR ⁵ ;
G ¹ , G ² and G ³ are the same or different and are selected from the group consisting of OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
X ³ is halogen, OR ¹⁵ , SR ¹⁵ , NR ¹⁵ R ¹⁶ , OSO ₂ R ¹⁵ or NHSO ₂ R ¹⁵ ;
R ⁶ and R ⁷ are the same or different and are selected from the group consisting of hydrogen, an alkyl residue, an aryl residue, OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
R ⁵ , R ⁸ , R ⁹ , R ¹⁵ and R ¹⁶ are the same or different and are selected from the group consisting of hydrogen, alkyl residues and aryl residues),
A process for producing piperidine derivative compounds or salts thereof, which comprises converting this regioisomer into a piperidine derivative compound using a piperidine compound.

or

(In each formula above,
n is 0 or 1;
R ¹ is hydrogen or hydroxy;
R ² is hydrogen; or
when n is 0, R ¹ and R ² together form a second bond between the carbon atoms containing R ¹ and R ² ,
Provided that when n is 1, R ¹ and R ² are each hydrogen;
R ³ is -COOH or -COOR ⁴ ;
R ⁴ is an alkyl or aryl moiety;
A, B and D are substituents of each ring, each of which may be the same or different and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents)
[2" claim-type="Currently amended] According to claim 1, wherein the regioisomer is α, α-disubstituted-methylbenzene derivative having the formula

(Wherein
X ¹ is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, substituted sulfonic acid ester or substituent useful for organometallic coupling reaction) conditions effective for producing the above isomers Provided by acylation with a compound having the formula

or

(Wherein
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ¹⁰ is selected from the group consisting of hydrogen, alkyl residues and aryl residues)
[3" claim-type="Currently amended] The α, α-bisubstituted-methylbenzene derivative having the formula

further comprising reacting with a methylating agent under conditions effective to produce an α, α-disubstituted-methylbenzene derivative.
[4" claim-type="Currently amended] The compound of claim 3, wherein Z has the formula

Α, α-disubstituted benzyl acid derivative having the formula

further comprising reacting with an aminoalkyl derivative having the formula: under conditions effective to produce an α, α-disubstituted methylbenzene derivative.
H ₂ N- (CR ⁶ R ⁷ ) _m -QH
[5" claim-type="Currently amended] The compound of claim 2, wherein Z has the formula

Α, α-disubstituted benzyl acid derivative having the formula

further comprising reacting with an aminoalkyl derivative having the formula: under conditions effective to produce an α, α-disubstituted methylbenzene derivative.
H ₂ N- (CR ⁶ R ⁷ ) _m -QH
[6" claim-type="Currently amended] According to claim 1, wherein the regioisomer is a 4- (α, α-disubstituted)-toluic acid derivative having the formula

(Wherein
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ¹⁰ is selected from the group consisting of hydrogen, alkyl moieties and aryl moieties). A process provided by reacting a compound having the formula below under conditions effective to produce said regioisomer.

(Wherein
X ¹ is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, substituted sulfonic acid ester or substituent useful for organometallic coupling reactions)
[7" claim-type="Currently amended] The method of claim 6, wherein the 4- (α, α-ibsubstituted) -toluic acid derivative having the formula

Further comprising reacting with a methylating agent under conditions effective to produce a 4- (α, α-disubstituted) -toluic acid derivative.
[8" claim-type="Currently amended] 8. The compound of claim 7, wherein Z has the formula

4- (α-carboxy-α, α-bisubstituted) -toluic acid derivatives having the formula

Further comprising reacting with an aminoalkyl derivative having the formula: under conditions effective to produce a 4- (α, α-ibsubstituted) -toluic acid derivative.
H ₂ N- (CR ⁶ R ⁷ ) _m -QH
[9" claim-type="Currently amended] The compound of claim 6, wherein Z has the formula

4- (α-carboxy-α, α-disubstituted) -toluic acid derivatives having the formula

Further comprising reacting with an aminoalkyl derivative having the formula: under conditions effective to produce a 4- (α, α-disubstituted) -toluic acid derivative.
H ₂ N- (CR ⁶ R ⁷ ) _m -QH
[10" claim-type="Currently amended] The method of claim 1, wherein the regioisomer provides an α, α-disubstituted regioisomer precursor having the formula:

A method wherein the α, α-disubstituted regioisomer precursor is provided by methylation under conditions effective to produce the regioisomer.
[11" claim-type="Currently amended] The method of claim 10, wherein the α, α-disubstituted regioisomer precursor is a α, α-disubstituted-methylbenzene derivative having the formula

(Wherein
X ¹ is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, substituted sulfonic acid ester or substituent useful for organometallic coupling reactions)
A method provided by acylating a compound having the formula below under conditions effective to produce an α, α-disubstituted regioisomer precursor.

or

(Wherein
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ¹⁰ is selected from the group consisting of hydrogen, alkyl residues and aryl residues)
[12" claim-type="Currently amended] The method of claim 10, wherein the α, α-disubstituted regioisomer precursor is a 4- (α, α-disubstituted) -toluic acid derivative having the formula

(Wherein
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ¹⁰ is selected from the group consisting of hydrogen, alkyl moieties and aryl moieties.) A method provided by reacting a compound having the formula below under conditions effective to produce an α, α-disubstituted regioisomer precursor.

(Wherein
X ¹ is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, substituted sulfonic acid ester or substituent useful for organometallic coupling reactions)
[13" claim-type="Currently amended] The method of claim 1, further comprising reducing the piperidine derivative under conditions effective to form a hydroxylated piperidine derivative compound of the formula:

[14" claim-type="Currently amended] The method of claim 13, wherein the hydroxylated piperidine derivative compound has the formula:

[15" claim-type="Currently amended] The method of claim 13, wherein the hydroxylated piperidine derivative compound has the formula:

[16" claim-type="Currently amended] The method of claim 1 wherein the piperidine derivative compound has the formula:

[17" claim-type="Currently amended] The method of claim 1, wherein the pyridine derivative compound has the formula:

[18" claim-type="Currently amended] The method of claim 1, wherein the conversion is a regioisomer having the formula

A first intermediate compound having the formula

By hydrolysis under conditions effective to form.
[19" claim-type="Currently amended] 19. The process of claim 18, wherein the conversion comprises combining the first intermediate compound with a piperidine compound of the formula

A process carried out by reacting under conditions effective to form a piperidine derivative compound of the formula:

[20" claim-type="Currently amended] 19. The process of claim 18, wherein the conversion esterifies the first intermediate compound to its ester having the formula

This ester is a piperidine compound of the formula

Under conditions effective to form a piperidine derivative compound having the formula
Further comprising reacting.

[21" claim-type="Currently amended] The method of claim 20, wherein the piperidine derivative compound of the formula

And hydrolyzing with a piperidine derivative compound of the formula:

[22" claim-type="Currently amended] 19. The compound of claim 18, wherein n is 1 and the conversion is conducted to react the first intermediate compound under conditions effective to produce 4-hydroxypiperidine and N-substituted hydroxypiperidine having the formula:

The resulting N-substituted hydroxypiperidine and diphenylhalomethane having the formula

Wherein X ⁴ is halogen
Further comprising reacting under conditions effective to form a piperidine compound derivative of the formula:

[23" claim-type="Currently amended] The method according to claim 1, wherein the conversion is a piperidine compound having the formula

And reacting under conditions effective to form a piperidine derivative precursor having the formula:

[24" claim-type="Currently amended] The method of claim 23, further comprising converting the piperidine derivative precursor to a piperidine derivative compound having the formula:

[25" claim-type="Currently amended] 24. The method of claim 23, further comprising reducing the piperidine derivative precursor under conditions effective to form a hydroxylated piperidine derivative precursor of the formula:

[26" claim-type="Currently amended] 26. The method of claim 25, further comprising converting the hydroxylated piperidine derivative precursor to a hydroxylated piperidine derivative compound of the formula:

[27" claim-type="Currently amended] The process according to claim 1, wherein n is 1 and the conversion is carried out under conditions effective to produce the regioisomer with 4-hydroxypiperidine and N-substituted-hydroxypiperidine having the formula:

The resulting N-substituted hydroxypiperidine and diaryl halomethane having the formula

Wherein X ⁴ is halogen
Further comprising reacting under conditions effective to form a piperidine derivative precursor of the formula:

[28" claim-type="Currently amended] 28. The method of claim 27, further comprising converting the piperidine derivative precursor to a piperidine derivative compound having the formula

[29" claim-type="Currently amended] 28. The method of claim 27, further comprising reducing the piperidine derivative precursor under conditions effective to form a hydroxylated piperidine derivative precursor of the formula:

[30" claim-type="Currently amended] 30. The method of claim 29, further comprising converting the hydroxylated piperidine derivative precursor to a hydroxylated piperidine derivative compound of the formula:

[31" claim-type="Currently amended] It provides an α, α-disubstituted-methylbenzene derivative having the formula

(Wherein
Z is -CG ¹ G ² G ³ ,
or ego;
m is an integer from 1 to 6;
Q and Y are the same or different and are selected from the group consisting of O, S and NR ⁵ ;
G ¹ , G ² and G ³ are the same or different and are selected from the group consisting of OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
X ¹ is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, substituted sulfonic acid ester or substituent useful for organometallic coupling reactions;
R ⁶ and R ⁷ are the same or different and are selected from the group consisting of hydrogen, an alkyl residue, an aryl residue, OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
R ⁵ , R ⁸ and R ⁹ are the same or different and are selected from the group consisting of hydrogen, alkyl residues and aryl residues)
A method for producing a piperidine derivative compound having the following formula comprising converting the α, α-disubstituted-methylbenzene derivative into a piperidine derivative using a piperidine compound.

or

(Wherein
n is 0 or 1;
R ¹ is hydrogen or hydroxy;
R ² is hydrogen; or
when n is 0, R ¹ and R ² together form a second bond between the carbon atoms containing R ¹ and R ² ,
Provided that when n is 1, R ¹ and R ² are each hydrogen;
R ³ is -COOH or -COOR ⁴ ;
R ⁴ is an alkyl or aryl moiety;
A, B and D are substituents of each ring, each of which may be the same or different and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents)
[32" claim-type="Currently amended] 32. The method of claim 31, wherein the α, α-disubstituted-methylbenzene derivative is prepared under the conditions effective to produce the α, α-disubstituted-methylbenzene derivative having the formula: Provided by reacting with a topical agent.

[33" claim-type="Currently amended] 33. The compound of claim 32, wherein Z has the formula

Α, α-disubstituted benzyl acid derivative having the formula

further comprising reacting with an aminoalkyl derivative having the formula: under conditions effective to produce an α, α-disubstituted methylbenzene derivative.
H ₂ N- (CR ⁶ R ⁷ ) _m -QH
[34" claim-type="Currently amended] The compound of claim 31, wherein Z has the formula

The α, α-disubstituted methylbenzene derivative is an α, α-disubstituted benzyl acid derivative having the formula

A method provided by reacting an aminoalkyl derivative having the formula below under conditions effective to produce said α, α-disubstituted methylbenzene derivative.
H ₂ N- (CR ⁶ R ⁷ ) _m -QH
[35" claim-type="Currently amended] 32. The method of claim 31, further comprising reducing the piperidine derivative under conditions effective to form a hydroxylated piperidine derivative compound of the formula:

[36" claim-type="Currently amended] 36. The method of claim 35, wherein the hydroxylated piperidine derivative compound has the formula

[37" claim-type="Currently amended] 36. The method of claim 35, wherein the hydroxylated piperidine derivative compound has the formula

[38" claim-type="Currently amended] 32. The method of claim 31, wherein the piperidine derivative compound has the formula

[39" claim-type="Currently amended] 32. The method of claim 31, wherein the pipyredin derivative compound has the formula:

[40" claim-type="Currently amended] 32. The method of claim 31, wherein the conversion is 4- (4-substituted) piperidin-1-yl) butanal or 4- (4-substituted) -pi having the formula Ferridin-1-yl) butyric acid derivative

(Wherein
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ¹⁰ is selected from the group consisting of hydrogen, alkyl residues and aryl residues)
A process performed by reacting under conditions effective to form a piperidine derivative precursor having the formula:

[41" claim-type="Currently amended] 41. The method of claim 40, wherein said conversion comprises a piperidine derivative precursor of the formula

A method carried out by hydrolysis under conditions effective to form a piperidine derivative having the formula:

[42" claim-type="Currently amended] 32. The compound according to claim 31, wherein n is 1 and the conversion is an α, α-disubstituted-methylbenzene derivative having 4- (4-substituted-piperidin-1-yl) butanal or 4- (4 -Substituted-piperidin-1-yl) butyric acid derivatives

(Wherein
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ¹⁰ is selected from the group consisting of hydrogen, alkyl residues and aryl residues)
Reacting under conditions effective to produce N-substituted hydroxypiperidine having the formula:

The resulting N-substituted hydroxypiperidine was prepared using diarylhalomethane having the formula

Wherein X ⁴ is halogen
A process performed by converting under conditions effective to form a piperidine derivative compound of the formula:

[43" claim-type="Currently amended] It provides 4- (α, α-disubstituted) -toluic acid derivatives having the formula:

(Wherein
Z is -CG ¹ G ² G ³ ,
or ego;
m is an integer from 1 to 6;
Q and Y are the same or different and are selected from the group consisting of O, S and NR ⁵ ;
G ¹ , G ² and G ³ are the same or different and are selected from the group consisting of OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ⁶ and R ⁷ are the same or different and are selected from the group consisting of hydrogen, an alkyl residue, an aryl residue, OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
R ⁵ , R ⁸ , R ⁹ and R ¹⁰ are the same or different and are selected from the group consisting of hydrogen, alkyl residues and aryl residues)
A method for producing a piperidine derivative compound represented by the following formula comprising converting this 4- (α, α-disubstituted) -toluic acid derivative into a piperidine derivative using a piperidine compound.

or

(Wherein
n is 0 or 1;
R ¹ is hydrogen or hydroxy;
R ² is hydrogen; or
when n is 0, R ¹ and R ² together form a second bond between the carbon atoms containing R ¹ and R ² ,
Provided that when n is 1, R ¹ and R ² are each hydrogen;
R ³ is -COOH or -COOR ⁴ ;
R ⁴ is an alkyl or aryl moiety;
A, B and D are substituents of each ring, each of which may be the same or different and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents)
[44" claim-type="Currently amended] 44. The method of claim 43, wherein the 4- (α, α-disubstituted) -toluic acid derivative has a 4- (α, α-disubstituted) -toluic acid derivative having the formula

Provided by reacting with a methylating agent under conditions effective to produce said 4- (α, α-disubstituted) -toluic acid derivative.
[45" claim-type="Currently amended] 45. The compound of claim 44, wherein Z has the formula

4- (α-carboxy-α, α-bisubstituted) toluic acid derivatives having the formula

Further comprising reacting with an aminoalkyl derivative having the formula: under conditions effective to produce a 4- (α, α-ibsubstituted) -toluic acid derivative.
H ₂ N- (CR ⁶ R ⁷ ) _m -QH
[46" claim-type="Currently amended] The compound of claim 43, wherein Z has the formula

The 4- (α, α-disubstituted) -toluic acid derivative has a 4- (α-carboxy-α, α-disubstituted) -toluic acid derivative having the formula

A method provided by reacting with an aminoalkyl derivative having the formula below under conditions effective to produce a 4- (α, α-disubstituted) -toluic acid derivative.
H ₂ N- (CR ⁶ R ⁷ ) _m -QH
[47" claim-type="Currently amended] 44. The method of claim 43, further comprising reducing the piperidine derivative compound under conditions effective to form a hydroxylated piperidine derivative compound of the formula:

[48" claim-type="Currently amended] 48. The method of claim 47, wherein the hydroxylated piperidine derivative compound has the formula:

[49" claim-type="Currently amended] 48. The method of claim 47, wherein the hydroxylated piperidine derivative compound has the formula:

[50" claim-type="Currently amended] 44. The method of claim 43, wherein the piperidine derivative compound has the formula

[51" claim-type="Currently amended] 44. The method of claim 43, wherein the pypyredin derivative compound has the formula:

[52" claim-type="Currently amended] 44. The method of claim 43, wherein the conversion comprises 4- (α, α-disubstituted) toluic acid with 3- (4-substituted) piperidin-1-yl) propane derivative having the formula

(Wherein
X ¹ is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, substituted sulfonic acid ester or substituent useful for organometallic coupling reactions)
A process performed by reacting under conditions effective to produce a piperidine derivative precursor having the formula:

[53" claim-type="Currently amended] 53. The method of claim 52, wherein said conversion comprises a piperidine derivative precursor having the formula

And hydrolyzing under conditions effective to form a piperidine derivative having the formula:

[54" claim-type="Currently amended] 44. The compound of claim 43, wherein n is 1, and the conversion is a 4-( , -Disubstituted) toluic acid derivative with

(Wherein
X ¹ is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, substituted sulfonic acid ester or substituent useful for organometallic coupling reactions)
Reacting under conditions effective to produce N-substituted hydroxypiperidine having the formula:

The resulting N-substituted hydroxypiperidine was prepared using diarylhalomethane having the formula

Wherein X ⁴ is halogen
A process carried out by converting under conditions effective to form a piperidine derivative of the formula

[55" claim-type="Currently amended] Regioisomers having the formula:

(Wherein
Z is -CG ¹ G ² G ³ ,
or ego;
m is an integer from 1 to 6;
Q and Y are the same or different and are selected from the group consisting of O, S and NR ⁵ ;
G ¹ , G ² and G ³ are the same or different and are selected from the group consisting of OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
X ³ is halogen, OR ¹⁵ , SR ¹⁵ , NR ¹⁵ R ¹⁶ , OSO ₂ R ¹⁵ or NHSO ₂ R ¹⁵ ;
R ⁶ and R ⁷ are the same or different and are selected from the group consisting of hydrogen, an alkyl residue, an aryl residue, OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
R ⁵ , R ⁸ , R ⁹ , R ¹⁵ and R ¹⁶ are the same or different and are selected from the group consisting of hydrogen, alkyl residues and aryl residues;
A is a ring substituent, each of which may be the same or different and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents)
[56" claim-type="Currently amended] The compound of claim 55, wherein Z is
Phosphorus isomer.
(Wherein R ⁶ and R ⁷ are each methyl and R ¹² and R ¹³ are each hydrogen)
[57" claim-type="Currently amended] Α, α-disubstituted-methylbenzene derivatives having the formula

(Wherein
X ¹ is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, substituted sulfonic acid ester or substituent useful for organometallic coupling reactions) A compound having the formula

or

(Wherein
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ¹⁰ is selected from the group consisting of hydrogen, alkyl residues and aryl residues).

(Wherein
Z is -CG ¹ G ² G ³ ,
or ego;
m is an integer from 1 to 6;
Q and Y are the same or different and are selected from the group consisting of O, S and NR ⁵ ;
G ¹ , G ² and G ³ are the same or different and are selected from the group consisting of OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
X ³ is halogen, OR ¹⁵ , SR ¹⁵ , NR ¹⁵ R ¹⁶ , OSO ₂ R ¹⁵ or NHSO ₂ R ¹⁵ ;
R ⁶ and R ⁷ are the same or different and are selected from the group consisting of hydrogen, an alkyl residue, an aryl residue, OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
R ⁵ , R ⁸ , R ⁹ , R ¹⁵ and R ¹⁶ are the same or different and are selected from the group consisting of hydrogen, alkyl residues and aryl residues;
A is a ring substituent, each of which may be the same or different and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents)
[58" claim-type="Currently amended] 58. The method of claim 57, further comprising reacting the α, α-disubstituted-methylbenzene derivative having the formula: with a methylating agent under conditions effective to produce the α, α-disubstituted-methylbenzene derivative.

[59" claim-type="Currently amended] 59. The compound of claim 58, wherein Z has the formula

Α, α-disubstituted benzyl acid derivative having the formula

further comprising reacting with an aminoalkyl derivative having the formula: under conditions effective to produce an α, α-disubstituted methylbenzene derivative.
H ₂ N- (CR ⁶ R ⁷ ) _m -QH
[60" claim-type="Currently amended] The compound of claim 57, wherein Z has the formula

Α, α-disubstituted benzyl acid derivative having the formula

further comprising reacting with an aminoalkyl derivative having the formula: under conditions effective to produce an α, α-disubstituted methylbenzene derivative.
H ₂ N- (CR ⁶ R ⁷ ) _m -QH
[61" claim-type="Currently amended] To provide an α, α-disubstituted regioisomer precursor having the formula

A method of preparing a legitimer of formula (I), comprising methylating the α, α-disubstituted regioisomer precursor under conditions effective to produce the legioisomer.

(Wherein
Z is -CG ¹ G ² G ³ ,
or ego;
m is an integer from 1 to 6;
Q and Y are the same or different and are selected from the group consisting of O, S and NR ⁵ ;
G ¹ , G ² and G ³ are the same or different and are selected from the group consisting of OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
X ³ is halogen, OR ¹⁵ , SR ¹⁵ , NR ¹⁵ R ¹⁶ , OSO ₂ R ¹⁵ or NHSO ₂ R ¹⁵ ;
R ⁶ and R ⁷ are the same or different and are selected from the group consisting of hydrogen, an alkyl residue, an aryl residue, OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
R ⁵ , R ⁸ , R ⁹ , R ¹⁵ and R ¹⁶ are the same or different and are selected from the group consisting of hydrogen, alkyl residues and aryl residues;
A is a ring substituent, each of which may be the same or different and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents)
[62" claim-type="Currently amended] 62. The α, α-disubstituted regioisomer precursor of claim 61, wherein the α, α-disubstituted regioisomer precursor has

(Wherein
X ¹ is hydrogen, halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, substituted sulfonic acid esters or substituents useful in organometallic coupling reactions)
A compound having the formula

or

(Wherein
X ² is halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ¹⁰ is selected from the group consisting of hydrogen, alkyl moieties and aryl moieties).
[63" claim-type="Currently amended] 62. The method of claim 61, wherein the α, α-disubstituted regioisomer precursor is a 4- (α, α-ibsubstituted) -toluic acid derivative having the formula

(Wherein
X ² is halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ¹⁰ is selected from the group consisting of hydrogen, an alkyl moiety and an aryl moiety) provided by acylating a compound having the formula below under conditions effective to produce said α, α-disubstituted regioisomer precursor.

(Wherein
X ¹ is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, substituted sulfonic acid ester or substituent useful for organometallic coupling reactions)
[64" claim-type="Currently amended] 4- (α, α-disubstituted) -toluic acid derivatives having the formula

(Wherein
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ¹⁰ is selected from the group consisting of hydrogen, alkyl moieties and aryl moieties) Compounds having the formula below under conditions effective to produce the regioisomer

(Wherein
X ¹ is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, substituted sulfonic acid ester or substituent useful for organometallic coupling reactions) The manufacturing method of the regioisomer of this.

(Wherein
Z is -CG ¹ G ² G ³ ,
or ego;
m is an integer from 1 to 6;
Q and Y are the same or different and are selected from the group consisting of O, S and NR ⁵ ;
G ¹ , G ² and G ³ are the same or different and are selected from the group consisting of OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
X ³ is halogen, OR ¹⁵ , SR ¹⁵ , NR ¹⁵ R ¹⁶ , OSO ₂ R ¹⁵ or NHSO ₂ R ¹⁵ ;
R ⁶ and R ⁷ are the same or different and are selected from the group consisting of hydrogen, an alkyl residue, an aryl residue, OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
R ⁵ , R ⁸ , R ⁹ , R ¹⁵ and R ¹⁶ are the same or different and are selected from the group consisting of hydrogen, alkyl residues and aryl residues;
A is a ring substituent, each of which may be the same or different and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents)
[65" claim-type="Currently amended] 65. The method of claim 64, wherein the 4- (α, α-disubstituted) -toluic acid derivative having the formula is reacted with a methylating agent under conditions effective to produce 4- (α, α-disubstituted) -toluic acid derivative How to include more.

[66" claim-type="Currently amended] 66. The compound of claim 65, wherein Z has the formula

4- (α-carboxy-α, α-bisubstituted) -toluic acid derivatives having the formula

Further comprising reacting with an aminoalkyl derivative having the formula: under conditions effective to produce a 4- (α, α-ibsubstituted) -toluic acid derivative.
H ₂ N- (CR ⁶ R ⁷ ) _m -QH
[67" claim-type="Currently amended] The compound of claim 64, wherein Z has the formula

4- (α-carboxy-α, α-disubstituted) -toluic acid derivatives having the formula

Further comprising reacting with an aminoalkyl derivative having the formula: under conditions effective to produce a 4- (α, α-disubstituted) -toluic acid derivative.
H ₂ N- (CR ⁶ R ⁷ ) _m -QH
[68" claim-type="Currently amended] 4- (α, α-disubstituted) -toluic acid derivatives having the formula:

(Wherein
Z is -CG ¹ G ² G ³ ,
or ego;
m is an integer from 1 to 6;
Q and Y are the same or different and are selected from the group consisting of O, S and NR ⁵ ;
G ¹ , G ² and G ³ are the same or different and are selected from the group consisting of OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ⁶ and R ⁷ are the same or different and are selected from the group consisting of hydrogen, an alkyl residue, an aryl residue, OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
R ⁵ , R ⁸ , R ⁹ and R ¹⁰ are the same or different and are selected from the group consisting of hydrogen, alkyl residues and aryl residues;
A is a ring substituent, each of which may be the same or different and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents)
[69" claim-type="Currently amended] 69. The compound of claim 68, wherein Z is

(Wherein R ⁶ and R ⁷ are each methyl and R ¹² and R ¹³ are each hydrogen) and 4- (α, α-disubstituted) wherein X ² is N (CH ₃ ) (OCH ₃ ) Toluic acid derivatives.
[70" claim-type="Currently amended] 4- (α, α-ibsubstituted) -toluic acid derivatives having the formula:

(Wherein
Z is -CG ¹ G ² G ³ ,
or ego;
m is an integer from 1 to 6;
Q and Y are the same or different and are selected from the group consisting of O, S and NR ⁵ ;
G ¹ , G ² and G ³ are the same or different and are selected from the group consisting of OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
X ² is hydrogen; halogen; Alkali metal oxides; Residues of formula -OR ¹⁰ ; Residues of the formula -SR ¹⁰ ; Or an amine;
R ⁶ and R ⁷ are the same or different and are selected from the group consisting of hydrogen, an alkyl residue, an aryl residue, OR ⁸ , SR ⁸ and NR ⁸ R ⁹ ;
R ⁵ , R ⁸ , R ⁹ and R ¹⁰ are the same or different and are selected from the group consisting of hydrogen, alkyl residues and aryl residues;
A is a ring substituent, each of which may be the same or different and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents)
[71" claim-type="Currently amended] 71. The compound of claim 70, wherein Z is

(Wherein R ⁶ and R ⁷ are each methyl and R ¹² and R ¹³ are each hydrogen) and X ( ² ) is 4- (α, α-ibichi, wherein N ² is N (CH ₃ ) (OCH ₃ ) Cyclic) -toluic acid derivatives.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
1995-12-21|Priority to US08/575,344

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1995-12-21|Priority to US8/575,344

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1995-12-21|Priority to US08/575,344

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1996-12-19|Application filed by 알바니 몰레큘라 리써치, 인크.

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1996-12-19|Priority to PCT/US1996/020769

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2000-11-06|Publication of KR20000064507A

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2005-11-25|Application granted

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2005-11-25|Publication of KR100516869B1

优先权:

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申请号 | 申请日 | 专利标题

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US08/575,344|1995-12-21|

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US8/575,344|1995-12-21|

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US08/575,344|US6201124B1|1995-12-21|1995-12-21|Process for production of piperidine derivatives|

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PCT/US1996/020769|WO1997022344A1|1995-12-21|1996-12-19|Process for production of piperidine derivatives|