JPH06502849A - Method for producing polycyclic oxygen-containing cyclic component - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Method for producing polycyclic oxygen-containing cyclic component Background of the invention The present invention is based on pending U.S. patent application Ser. No. 07/620.240 (1990, Nov. This is a partial continuation application of the previous application.

field of invention The present invention has unique CNS, anti-emetic and gastric pro-active properties. 5HTs-antagonistic properties including kinettcactivity) dibenzofuran and penzofuran, which have no significant islet receptor binding affinity. It relates to polycyclic oxygen-containing cyclic compounds such as sosine-type compounds. The present invention also provides This invention relates to stereoselective methods for producing, separating, and purifying compounds.

5-Hydroxytryptamine (abbreviated as “5-HT”) is a serotonin It is commonly known. Serotonin is distributed throughout the body, including the gastrointestinal tract, platelets, spleen, and brain. found in the brain's species of neurons, which are involved in many physiological processes such as neurotransmission. It is thought to play a role in the development of neurotransmitters and is associated with a number of central nervous system (CNS) diseases. moreover , serotonin is thought to act as a local hormone in the nerve periphery; It is released in the intestinal tract, improves the motility of the small intestine, inhibits the motility of the stomach and large intestine, and reduces gastric acid. Stimulate generation. Serotonin is thought to be involved in normal intestinal spiral movement.

Various physiological activities caused by serotonin occur on the surface of cells of different body tissues. Associated with various receptors found in membranes. Group 1 serotonin receptors contains two pharmacologically distinct receptors found in the ileum of guinea pigs. there was. “D” receptors mediate smooth muscle contraction, and M” receptors mediate cholinergic contraction. It is involved in the depolarization of erectile nerves and the release of acetylcholine. So far, 3 types Different groups of serotonin receptors have been identified, including: Designations have been proposed: D-receptor to 5-HT=-receptor; M-receptor 5-HT, -receptor; obviously neither 5-H"L nor 5-HT, etc. All receptors of It is.

5-HTs--receptors have been associated with non-neural tissues, brain tissues, and different responses. Present in many peripheral tissues. 5 HTs-receptors are attached to peripheral neurons. It has been reported that serotonin exists and is related to the (excitatory) depolarizing effects of serotonin. Ru. The following subtypes of 5-HT,-receptor activity have been reported: Postganglionic cells leading to depolarization and release of noradrenaline and acetylcholine, respectively. Effects involving sympathetic and parasympathetic neurons (5HTsa subtype); Tonin regulates acetylcholine concentration, action on enteric neurons (5-HT , C subtype): involved in stimulating the nerve endings of the heart and causing reflex bradycardia. effects on sensory nerves (5-HT, A subtype) and pain perception Effects on sensory nerves involved in sensation.

Highly selective 5HTs-antagonists can be used for chemotherapy and radiotherapy in cancer patients. known to be extremely effective in controlling and preventing vomiting caused by It is being 5-HTi-amplification in animals exposed to cancer chemotherapy and radiation. The antiemetic effects of antagonists are similar to those seen following abdominal vagotomy. ing. This antagonist compound inhibits vagal afferents to the vomiting-aligned region of the brainstem. Blocks the 5HTm-receptor present in the cell membrane of the tissue that forms the input. It is thought that it works by

Serotonin is also thought to be involved in the condition known as migraine. of the head Serotonin released locally within the vessel wall interacts with elements of the peripheral vascular plexus It is thought that the trigeminal nerve system's nerve-cum-afferent substance P-containing fibers are responsible for this state. It is thought to be related to by activating specific areas of sensory nerve endings. serotonin can be used to treat pain directly and also by other agents, such as bradykinin. It is thought that this occurs indirectly by increasing the painful effects of inflammatory media. As a result of stimulation of the atrial neuron that has been Then, there is a local release of substance P and possibly other sensory media, which leads to further vascular changes and contribute to migraines. Serotonin should be applied to the exposed blister base. It is known to cause pain when administered or after subcutaneous injection, and bradykinin It is known to greatly increase the pain response to In either case, pain The message requires specific 5-HT, -receptors on the first afferent neuron. It is considered to be essential.

In addition, 5-HT3-antagonist has been reported to exhibit antipsychotic effects. and is thought to be associated with anxiety. Although not fully understood, this The effect is an indirect proton of serotonin 5-HTs-mediated transformation of dopamine activity, It is believed to be related to

Numerous researchers have explored various compounds with 5-HT3-antagonist activity. are doing.

The development of SHTm agents is commercially available in high doses for the treatment of nausea and vomiting. Metoclopramide (Beacham Maxolone, A, H. Robins Reglan) Originating from research conducted using Metoclopramide has a weak 5HTs-a is a dopamine antagonist with antagonistic activity, and at high doses even more become noticeable. 5-HT, an active and non-dopamine antagonist, has primarily anti-emetic properties. It has been reported that this contributes to Other researchers have found that vomiting with migraine and We are investigating this compound in relation to pain.

Merel Dow's compound MDL-72222 is effective as an acute treatment for migraines However, toxicity issues have led to the end of research on this compound. It is reported that the Currently, there are four types of compounds: A, H, and Robbins' Zakoply. BRL-43694 of Beecham, GR-38032F of Gracs and San Doc's IC8-205-930 is used to treat nausea and vomiting caused by chemotherapy. It is currently undergoing clinical trials. GR-38032F has also been shown to be effective in anxiety and schizophrenia. Zacopride is in clinical trials for anxiety, with IC8- 205-930 has been shown to be effective in treating carcinoid syndrome.

Compounds reported as gastric stimulants include Beecham's BRL-249; 24, which are gastrointestinal motility disorders such as gastroparesis, auditory esophagitis, and gastrointestinal motility disorders. It has serotonin activity 311 and has 5-HTs-antagonist activity. It is also known to do.

Metoclopramide, Zacopride, Cizapride and BRL-24924 are 2 - carboxyl located para to the amine group of chloro-5-methoxyaniline Characterized by a mido group. BRL-43694, IC5-205-930, GR-38032F and GR-65630 are indole or N-methylindo It is characterized by a carbonyl group in the 3-position of the metal. MDL-72222 is Bridged azabicyclic 2,4-dichlorobenzoate, zacopride , BRL-2A 924, BRL-43694 and IC8-205-930, Bridged azabicyclic groups in the form of carboxamides or carboxylic acid esters has. Bicyclic oxygen-containing groups in which the carboxamide is ortho to the cyclic oxygen group Ruboxamide compound has antiemetic and antipsychotic properties according to EPO publication Th Reported in O234872.

Some of the reported compounds were synthesized using chiral synthesis, i.e., asymmetric introduction synthetic methods. There are stereoisomers that are In general, asymmetric introduction syntheses are known in the art. . Asymmetric introduction synthesis is a process in which a chiral structure is created throughout the substrate molecule by reaction with an achiral unit. molecules so that the stereoisomeric products are produced in equal amounts defined as the process of manufacturing Such asymmetric synthesis is only possible with one type of dias Eliminate unwanted isomers when teleomers are useful or interesting There is great economic value in reducing the amount of waste.

The reactants used in asymmetric synthesis include at least one catalyst consisting of reagents, solvents, or catalysts. It can be a natural ingredient. Alternatively, select specific enantiomers as starting materials By doing so, more preferred stereoisomers can be derived. , selecting enantiomerically pure intermediates is not necessarily stereoselective. It cannot be said that it brings about synthesis. This is because the chirality of the intermediate is one or This is because it may be lost due to racemization under multiple reaction conditions.

Therefore, synthetic processes generally involve special steps to achieve stereoselective results. and a lengthy recrystallization process.

Reported progress U.S. Patent Nos. 4.859.683, 4.857.517, 4.924.0 No. 10 and No. 4.863.921 (all assigned to the same assignee as the present application) ) has been reported to have 5-HT, -antagonist and gastric activity promoting activity. The enantiomeric dibenzofurancarboxamide and 2-carboxylic acid Chromatographic separation and crystallization steps for the synthesis of samide-substituted benzoxebines It has been reported.

U.S. Pat. No. 4,863,921 describes the synthesis of dibenzofuran carboxamides. , an amine represented by the general formula H,NR, and a substituted dibenzofuran-4-carboxylic acid Or 6. 7. 8. 9-tetrahydrodibenzofuran-4-carboxylic acid or 5a.

6, 7. 8. 9. 9a-hexahydrodibenzofuran-4-carboxylic acid or by condensation with these acid chlorides or esters to form the corresponding carboxyl I'm getting Mido. This method involves flash chromatographic separation of isomers and reconsolidation. Although crystallization is being carried out, the overall yield is low. This synthesis is performed under mildly acidic conditions and is racemic. This becomes difficult in the presence of acid-sensitive chiral centers.

The present invention provides stereoselective synthesis using conditions that do not affect the chiral centers of the product. is based on the discovery that acid-sensitive intermediates can be used in . Using the method of the invention, known separation techniques can be used to obtain the desired enantiomers. Synthesize specific stereoisomers of two basic fused bridged ring systems without using be able to. The compound synthesized by this method was published on November 29, 1990. Pending U.S. Patent Application No. 07/620, filed and named to Assignee It is described and claimed in No. 241.

Summary of the invention The present invention provides polycyclic acids having at least two chiral centers in fused or bridged ring positions. The present invention relates to a method for producing a substantially optically pure compound having an elemental content. present invention A preferred compound prepared by is represented by formula I.

Formula I In the formula, one of A or B is CHR, and the other A or B is a single bond.

Y is CHR.

n is 0. 1 or 2.

Ro is hydroxo, alkoxy, aralkoxy, halo, OM (M is alkaline potassium or alkaline earth metal), or NH-X, where X is hydrogen, alkali , acyl or Z, and Z is and its stereoisomers 2 R and RI are independently hydrogen, alkyl, halo, alkoxy, aryl, aral Kyl, haloalkyl, amino, alkylamino, sulfonyl, alkylsulfa is mil or alkylsulfonyl; Rt, Rs, R4, Rs and R1 are independently hydrogen, alkyl, halo, alco is xy, aryl, aralkyl or haloalkyl; adjacent Rt, Rs , Ra, R3 and R0 groups may jointly form a double bond.

Compounds of formula I preferably contain a cycloalkenyl having a chiral center in the 3-position. salicylic acid, ester, amide, acid chloride or salt with the chiral center. Produced by subjecting the loalkenyl substituent to non-racemizing acidic cyclization conditions .

A preferred embodiment of the present invention is the stereoselective synthesis of a compound represented by the following formula (1) or (2). It is.

Formula ■ Formula ■ A further preferred embodiment of the present invention is the formation of an intermediate compound represented by the following formula (1) or (2). This is body-selective synthesis.

In the formula, Y is CH.

n is l.

Ro is hydroxy, alkoxy or NH-X (X is Z, and is its stereoisomer), R is hydrogen or halo: R3 is independently hydrogen, amino or mono- and di-alkylamino: R1, Ra　, R4, R, s and R6 are hydrogen: and adjacent R,,R,, The R, , R, and R6 groups may jointly form a double bond.

This method uses salicylic acid containing a cycloalkenyl having a chiral center in the 3-position, cycloalkenyl substitution of a ster, amide or derivative thereof with said chiral center Subjecting the group to acidic cyclization conditions that do not racemize it.

Detailed description of the invention As used above and as used in this specification, unless otherwise specified, the following: The terms shall have the following meanings:

-1 and -@fiml indicate the configuration of the chiral center.

"Alkyl", alone or within various substituents defined above, means from 1 to about IO refers to a hydrocarbon having 5 carbon atoms. “Lower alkyl” is, for example, methyl ethyl, propyl, isopropyl, butyl, isobutyl, amyl and hexyl means alkyl having from 1 to about 6 carbon atoms, such as Preferred lower grade Rukyl is methyl, ethyl and propyl.

"Halo" means C1, Br, I and F. Preferred zsoitc 1 and It is Br.

"Aryl" means substituted or unsubstituted mononuclear and polynuclear aromatic hydrocarbon groups.

Examples of preferred aryl groups are phenyl and naphthyl. Preferred substituents are: Hydrogen, alkyl, alkoxy, halo, aryl, aryloxy, carbo Alkoxy, nitro, dialkylamino, trifluoromethyl, thioalkyl and and carbamoyl.

"Aralkyl" means an alkyl group substituted with an aryl group. preferable Aralkyl groups are benzyl and phenethyl.

“Polycyclic” means one or more ring carbons replaced with nitrogen, oxygen or sulfur atoms. means a substituted or unsubstituted polynuclear aromatic hydrocarbon group.

Alkali or alkaline earth metals are metals that can form salts with carboxylic acids. means. Preferred metals are Na, Ca, Mg, Li and Cs.

The nomenclature used in this invention is shown in formulas Via~■.

Vla Vlb Vll V111 The present invention relates to a method for manipulating acid-sensitive chiral compounds under acidic conditions. It also enables a surprising method of synthesizing bridged or fused polycyclic compounds while maintaining their properties. It is. Further preferred compounds for use in the present invention are represented by formulas acid-sensitive carboxylic acids, esters, and amide chiral compounds. suitable acid cyclization By selecting the conditions, the method of the present invention enables the chiral formation of the following formulas IxEL and 3-cyclohexenyl salicylate of formulas XI and X11 synthesized from intermediates Compounds of formula (1) and/or V can be synthesized starting from

IX XI Xl+ The bridged ring compound of 2V is prepared by subjecting the corresponding compound of formula XI or Xll to sulfuric acid conditions, preferably or about 10 to about 50% aqueous sulfuric acid, most preferably about 35% aqueous sulfuric acid. Produced by leaving for about 5 minutes to about 12 hours, most preferably 30 minutes to about 2 hours. be able to.

The fused ring compound of formula It can be produced by simultaneously using a strong acid. Varying amounts of weak vs. strong acid By manipulating the ratio of fusion product IV to cross-linked product V from 6:1 to 1:1. be able to.

Additionally, the fusion product of formula ■ can be converted to the crosslinked product ■ using strong acid conditions. Can be done.

The following reaction schemes illustrate how to make compounds of the invention.

The following sea fence exemplifies the method of the invention.

(5xS, 9LS) (2S, 6R) This scheme is summarized below for the (R) chiral stereoisomer.

Stereospecific synthesis will be explained below with reference to the above reaction scheme.

(a) Esterification of 5-chlorosalicylic acid (1) to produce the corresponding pheno-/L (2) Get +.

(bl) The phenol is transported in a non-hydroxy non-racemizing polar medium (e.g. THF, DMF, acetonitrile, etc.), triphenylphosphine, dialkylazodica ruboxylate (preferably diethyl or dipropylazodicarboxylate) and upon treatment with pure chiral cyclohexene-3-(S)-oh/L (3) A chiral phenol cyclohexenylethenoha 4) is obtained.

FC+ This phenol cyclohexenyl ether is mixed with a base and a catalyst (e.g. C 52COs or 5i02) at a high temperature (100-250°C, preferably 150-250°C). When treated at 200°C), Claisen rearrangement occurs, resulting in 3-(3”-cyclohexyl) The chirality shifts to a new stereocenter of sen) salicylate (5).

It also includes neat or mono- and di-substituted anilines (e.g. dimethyl or di-substituted anilines). It can also be carried out in the presence of high boiling solvents such as ethylaniline or aromatic amines. Wear.

(d) 3-(3'-cyclohexenyl)salicylate, acetic acid, trifluoroacetic acid reflux with weak acids such as trifluoroacetic acid and sulfuric acid, hydrochloric acid, With a strong acid such as nitric acid, at -15 to 150°C (preferably at a slightly higher temperature (20 to 35°C)) Upon ring closure by treatment with ), chiral 5a, 6. 7. 8. 9.　 9a-Hexahydrodibenzofuran esterophor 6) and chiral 2,6-methano- 2H-(3,4゜5.6-tetrahydrof-1-penzoxocin-IO-ester 7) is obtained.

When this ring closure is performed using sulfuric acid alone, chiral 2,6-methano-28-C3゜4 ．． 5.6-tetrahydrof-1-penzoxocine-10-estenone 7) is the only can get.

tel This ester is preferably dissolved in an aqueous organic solvent (e.g. dioxane, in the presence of an alkali base (preferably NaO H.

Hydrolyze with an alkali base such as KOH or LiOH, most preferably LiOH) and dibenzofuranic acid as a salt (8) selectively from the salt of benzoctusic acid (9). isolated.

) Each group is replaced with a non-oxidizing mineral or organic acid, such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, etc. When treated with chiral dibenzofuranic acid (5aS, 9aS) Nzoctusic acid (2S,6R) (11) is obtained.

More specifically, it is most preferred to carry out this method using the desired ester. which is then converted into an acid, amide, acid chloride or salt of an acid under known reaction conditions. can be done.

In step (b), pure chiral 2-cyclohexene-1-(S)-ohno Pure chiral 2-cyclohexene-1-(R)-o/1 instead of 1-3) 45, the final chiral acid obtained is dibenzof Lanic acid (5aR, 9aR) α3 and chiral penzoxosinic acid (2R, 6S) (1 It is 4.

In this way, the need to separate the enantiomers of interest by tedious techniques is eliminated. There are four stereoisomers of dibenzofuran, eel, and benzokutsushi. Synthesize acids I and I as well as the corresponding esters, amides, acid chlorides, and salts. can do.

Resolution of the compounds of the invention and their starting materials can be carried out by known methods.

For example, U.S. Patent No. 4,863,921 and Volume 4 Introduction “0ptical R e5olutionProcedures for Chemical Com “pounds” (Optical Re5solution Information Amashishi ■ Center, l+tanhattan CoCo11e, Riverda LE, New York). Also, Enantiomers, Racemates and Re5 solutions” (Jean Ja eques, Andre CoP1et and Samuel H, Widen; John Wiley & 5ons, In c., New York, 1981) are also useful.

Basically, the resolution of compounds is based on differences in the physical properties of diastereomers. Ru. Mixtures of diastereomers form racemic compounds by attaching pure enantiomeric moieties into a form that can be separated by fractional crystallization, distillation or chromatography. Ru. Alternatively, another chiral center can be introduced into the desired product as shown below. You can also

Novel intermediate compounds of the present invention include compounds of formulas XIII-XV+.

X1ll XIV In the formula, Y is CHR; n is 0. l or 2; R" is halo, OM (M is an alkali or alkaline earth metal) or NH- X, X is hydrogen, alkyl, acyl or Z, and 2 is and its stereoisomer It is a sexual body: R and R are independently hydrogen, alkyl, halo, alkoxy, aryl, ara Alkyl, haloalkyl, amino, alkylamino, sulfonyl, alkylsulf amyl or alkylsulfonyl: Rt, R=, R-, Rs and R6 are , independently hydrogen, alkyl, halo, alkoxy, aryl, aralkyl or ha is loalkyl with the proviso that at least one of R8 is hydrogen and the adjacent R , , Rs, R, , R, and R6 groups may jointly form a double bond.

The compounds and methods of the invention are further illustrated by the following representative examples.

Example 1: Methyl 5-chlorosalicylate thionyl chloride (900.0 g; 7. 46 mol) was added to methanol (19 77.0 g; 61.72 mol) over 1 hour. Remove the cooling bath Then, 5-chlorosalicylic acid (1000.0 g; 5.8 mol) was added at once. , then gradually heated to reflux temperature. At the completion of this reaction, the solution is Cool at -5°C for 1 hour.

The produced methyl 5-chlorosalicylate was filtered off and cooled with methanol (-5°C; 1 50 ml) and deionized water (2X1. 934.1 by drying at 30°C for 24 hours under house vacuum) g (86%) of methyl 5-chlorosalicylate is obtained. rLp, 44-46 ℃. Elemental analysis (as C, H7CI01): C, H, calculated value C1: 19.0 0, Actual value C1: 1g, 50°) fPLc 97.87A! %.

Example 2: Methyl 5-chloro-2-(1''(S)-cycloheras-2-enyl) Salicylate 0.38 g methyl 5-chlorosalicylate and 0.4 g triphenate Place nilphosphine in a dry 3-meter flask and add anhydrous THF (20 ml). Add via cannula under nitrogen pressure. small amount (0.2 g) of 2-cyclohexene -1(S)-ol is added via syringe and the reaction mixture is cooled to 0<0>C. warm While maintaining the temperature at 0℃, add TIP (10 ml) and diethyl azodicarpoxylene-M. 0.23 g) was added dropwise over 1 hour. After the addition is complete, the reaction solution is Maintain at 0°C for 30 minutes, then warm to room temperature. Continue stirring for 3 hours. T.L. C (hexane:ethyl acetate 3:1) indicates that no starting material is present at this point. show. By evaporation of the solvent under reduced pressure and filtration of the oil through neutral alumina. 0.42 g (80%) methyl 5-chloro-2-(1 '(S)-cycloheras-2'-enyl)salicylate is obtained. Elemental analysis: Cu Calculated value as HuClOs C63,04, H5,67, actual value C62,61; H5, 67° BI-MS m/z: 266.268 (M” CI pattern ); 234.236(M”-(We); 80[(21”D=+101( C=0.1. (MeOH).

Example 3 Methyl 5-chloro-3-(3°(R)-cyclohekes-2′-enyl) Salicylate 0.42 g of the product of Example 2 above was mixed with 0.5 g of silica gel and It is sealed in a test tube together with 0.2 g of cesium carbonate under a nitrogen atmosphere. this exam Place the tube in an oil bath and heat at 150° C. for 5 hours. TLC (hexane: ethyl acetate 3:1) indicates the presence of the product and 5-chlorosalicylic acid. 5ml of iso Add propatool into the reaction mixture and pass the reaction mixture through a layer of Celite. Filter. This Celite layer is then further washed with 5 ml of isopropanol. . These isopropanol solutions were combined and evaporated to 1/3 of their volume, Put it in the freezer. After 12 hours, 0.2 g (50% yield) nochiral methyl 5-rioo-3-(3'(R)-shikuoheku7.-2'-work=ru)+rich Get a rate. Elemental analysis: Calculated value C63,04 as C+JLsC10s, H5, 67, actual value C64, 18, H5, 88° Bl-MS In/Z: 26 6.268 (M'' CI pattern); 234.236 (M'' (14e); [al　D=-95(C=0.1.MeOH).

0.2 g of the product from Example 3 above is dissolved in 6 ml of trifluoroacetic acid. then , 0.2 g of sulfuric acid is added. When this solution turns purple, reduce the temperature to 20°C. Increase the temperature from 25°C to 25°C. After stirring for 45 minutes, TLC (hexane:ethyl acetate 4 :l) indicates that only the product is present. Add 20ml of water to this reaction solution and stir for 10 minutes, then the mixture is extracted with 25 ml of toluene. The tor The ene solution was dried, filtered and evaporated under reduced pressure to give 0.2 g of the above furan ester. obtained as an amber oil.

This oily substance is methyl 2-oo-[5a(S)-9a(S)-(5a,6 ．． 7.8.9.9a-hexahydro)1dibenzofuran-4-carboxylate and methyl 8-chloro[2(S)-6(R))-methano-2H-3,4,5, 6-tetrahydro]-1-penzoxocine-10-carboxylate product 3 : Indicates that it is a mixture of 1.

Example 5: 2-chloro[5a(S)-9a(S)(5a, 6.7.8.9.9 a-hexahydro)]dibenzof 0.2 g of the 3:l mixture of Example 4 above was added to 2 m 1 of dioxane, 4 ml of 1N LiOH was added and the mixture was heated to 60 ml of dioxane. Heat to ℃. After 2 hours, TLC (hexane:ethyl acetate 4:1) showed only the acid. indicates the existence of This reaction solution was cooled in the refrigerator overnight to obtain 90μ of solid. , which is then acidified with an aqueous acetic acid solution. Extract this acetic acid solution with ethyl acetate, 60■2-chloroo[5a(S)-9a(SX5a, 6.7.8.9.9a- hexahydro)]]dibenzofuran-4-carvone is obtained. N, 0.150-1 53℃. Elemental analysis: Calculated value as C+5HuC10s C61,79,H5, 19, Actual value C61,74; H5,16゜El-MS m/z: 252.2 54 (M” CI pattern); 206.208 (M”-OMe), [al　D=-28(C=0.1.MeOH).

The LiOH solution of Example 5 was treated with aqueous acetic acid solution (20 ml) and ethyl acetate The product obtained was extracted with 8-chloro-[2(S)-6(R)-methanol- 2H-3,4,5,6-tetrahydro-1-penzoxocine 1-l local bond It is an acid.

Example 7 When the ring opening of Example 4 is carried out using only sulfuric acid, 8-chloro-[2(S)-6 (R)-Methano-2H-3,4,5,6-tetrahydro]-1-penzoxocine -l Local boxylate is formed. Hydrolysis with bases can cause inorganic or organic It provides a salt that is converted to the free acid when treated with organic acid. ILP, 120-122 ℃. Elemental analysis: Calculated value as C1J+5C1Os C61,79,H5,19 ;actual value C61.5? , H5, 12° [121”D=21(C=0.1. MeOH).

3-aminoquinuclidine (1.3 g, 0.011 DO1) was dissolved in methylene chloride (2 Dicyclohexylcarbodiimide (2.1 g, A solution of 0.011 mol) dissolved in methylene chloride (5 ml) is added. Next The mixture was then cooled to 0°C and 5-chlorosalicylic acid (1.7g, 0.0 098 mol) of methylene chloride solution was added and stirred overnight. Acetic acid (lrnf) to decompose excess synchhexylcarbodiimide and precipitate Filter off the chlorhexylurea. The resulting filtrate was diluted with IN sodium hydroxide and water. Wash, dry and concentrate to obtain the desired amide. Then, the (S) and (R ) to split the enantiomer.

5-Chlorosalicyl[N-(1-azabicyclo[2,2,2]octo-3(S) -Ilucarboxamide (0.56g, 0.002mol) and triphenyl Luphosphine (0.4 g) was charged into a dry 3-tubular flask and the crab was heated under nitrogen pressure. Add 20 ml of anhydrous THF via eureka. Small amount (0.2g) of 2-cyclo Add hexen-1(S)-ol via syringe and cool the reaction to 0°C. . A solution of 10 ml of T)IF and 0.23 g of diethyl azodicarboxylate is added dropwise over a period of 1 hour while maintaining the temperature at 0°C. After the addition is complete, this reaction The reaction solution is maintained at 0° C. for 30 minutes and then warmed to room temperature. Continue stirring for 3 hours Ru.

Evaporating the solvent under reduced pressure and filtering the oil through neutral alumina. 5-chloro-2-(1'(S)-cyclohekes-2'-enyl)salici [N-(1-azabicyclo[2,2,2]oct-3(S)-yl)]carbo Get xamide.

0.59 g (,0016 mol) of 5-chloro-2-(1'(S)-cyclohela) s-2°-enyl) salicyl[N-(1-azabicyclo[2,2,2]octo3 (S)-yl)1 carboxamide was added to 0.5 g of silica gel and and 0.2 g of cesium carbonate in a test tube. Place this test tube in an oil bath. and heat at 150°C for 5 hours. 51111 toluene was added to this reaction mixture. filter through a layer of Celite. Next, this celite layer is further coated with 5 layers. Wash with +nl of toluene. These toluene solutions were combined and IN sodium hydroxide was added. and water and evaporated to give 5-chloro-3-(3'(R)-cyclo hekes-2-enyl) salicyl[N, -(1-azabicyclo[2,2,2]oc To-3(S)-ylcarboxamide is obtained.

5-chloro-3-(3'(R)-cyclohekes-2'-enyl)salicyl[N -(1-azabicyclo[2°2.2]oct-3(S)-yl)]carboxami (0.28 g, 0007 mol) was dissolved in 6 ml of trifluoroacetic acid. , 0.4 g of sulfuric acid is added. After stirring for 45 minutes, 20ml of water was added to the reaction solution. and the resulting mixture was stirred for 10 minutes and then extracted with 25 ml of toluene. Ru. The toluene solution was dried and evaporated under reduced pressure to give 2-chloro-[5a(S )-9a(S)(5a, 6.7.8.9.9a-hexahydro)]]dibenzo Furan-4-N-(1-azabicyclo[2,2,21oct3(S)-yl)ka Ruboxamide and 8-chloro-[2(S)-6(R)-methano-2H-3,4,5 ,6-tetrahydro]-1-penzoxocine-10-[N-(1-azabicyclo [2,2,21oct-3(S)-yl)carboxamide was obtained, which These are separated by HPLC.

Example 12 Examples 8 to 1 by replacing 3-aminoquinuclidine with 3(R)-aminoquinuclidine Repeat step 1. The product thus prepared is 2-ri o rho[5a(S) -9a (SX5a, 6.7.8.9゜9a-hexahydrodibenzofuran- 4-(N-(1-azabicycloE2.2.21sucuto-3(R)-yl)carbo xamide and 8-chloro-[2(S)-6(R)-methano-2H-3,4,5 ,6-tetrahydro]-1-benzoxocine-10-[N-(1-azabicyclo [2,2,2]oct-3(R)-yl)carboxamide.

Example 13 Following the procedures of Examples 1-12, the methyl 5-chlorosalicylate of Example 2 was prepared as follows: In place of the compound in Table 1, the corresponding compound is thus prepared.

Methyl 5-bromosalicylate Methyl 5-methylsulfonylsalicylate Methyl 2-methoxy-4-amino-5 -chlorobenzoate methyl 2-methoxy-4-acetylamino-5-chlorobenzoate Methyl 2-methanezoate-4-acetylamino-5-chlorosalicylate Toxy-4-aminobenzoate methyl 2-methoxy-4-methylamino-5- Chlorobenzoate methyl 2-methoxy-5-sulf 7 milbenzoate!・Methi 2-methoxy-5-methylsulfamyl benzoate Example 14 Following the procedures of Examples 8 to 13, 3(S)-aminoquinuclidine/ of Example 8 was prepared as follows. Table below! In place of compound (2), the corresponding compound is thus prepared.

Table ll 3-aminoquinuclidine 4-amino-1-azabicyclo[3,3,11 nonane 4-amino-1-azabicyclo Chlo[2,2,2]octane 3-amino-9-methyl-9-azabicyclo[3, 3,1]nonane 3-amino-7-oxo-9-methyl-9-azabicyclo[3, 3,11 nonane 1-(p-fluorophenoxyprobyl)-3-methoxy-4- Aminopiperidine and stereoisomers of the above compounds.

Example 15 Following the procedure of Example 4, the ratio of weak acid (trifluoroacetic acid) to strong acid (sulfuric acid) was as follows: Fusion product (dibenzofuran) vs. crosslinked product (dibenzofuran) when varied according to Table III The relative ratios of benzoxazine) are shown in the table.

pain…work (hour) (ratio) (℃) Crosslinked product l TFν sulfuric acid (20:l) -s 6 /IITF cisulfuric acid (100:1) -s 6/12 7F cisulfuric acid (20:l) -ts 6/1 ■ Vinegar 1 Sulfuric acid (20:l) 25 1/1 Example 16 Add methyl 5-chloro- to concentrated sulfuric acid (519 ml) while maintaining the temperature below 50°C. 3-(3'cyclohexenyl)salicyre) (345g, 1.3+ool) Add little by little. After stirring for 1 hour at room temperature, the mixture was dissolved in water (4,21') and neutralize with 50% aqueous sodium hydroxide solution (843 ml). This basicity The mixture was extracted with toluene (2.5f) and the toluene phase was dried over sodium sulfate. Dry, filter and evaporate to dryness to give 351.6 g (102%) of methyl 8-chloro- 3,4,5,6-tetrahydro-2,6-methano-2H-1-penzoxocine- The 1O-carboxylate is obtained as an oil, which is used directly in the next step.

Methyl 8-chloro-3,4,5,6-tetrahydro-2,6-methano-2H-1 -Penzoxocine-10-carboxylate (351.6g) was added to lithium hydroxide. A solution of mu-hydrate (131.0 g, 3.12 added I) in water (2.61) and heat the mixture to reflux for 1.5 hours to form a heavy precipitate. . The reaction mixture was cooled to room temperature, ethyl acetate (1,71) was added and concentrated hydrochloric acid (276It) to acidify. The ethyl acetate was removed and the acidic aqueous phase was further treated with acetic acid. Extract with ethyl (500 ml). These ethyl acetate extracts were combined and diluted with sodium sulfate. Dry with thorium, filter and evaporate to dryness to obtain 327.7 g of material. Aceto Recrystallization from nitrile yielded 253.6 g of 8-chloro-3,4,5,6- Titrahydro 2,6-methano-2H+penzoxocin-1O-carboxylic acid was obtained. Ru. mp　110-120℃. +H-DCI,)δ! 0.94 (s, IH ); 7.98 (d, IH); 7.22 (d, IH); 4.98 ( s, IH): R. 10 (s, It(); 1.2-2.3 (a 8H).Achiral HPLC99,5 3A%.

2-chloro-cis-5a, 6.7.8.9.9a-hexahydrodibenzofura -4 to carboxylic acid (300 ml, 1.19 ml) and concentrated sulfuric acid (25 ml) ) is stirred at room temperature for 1 hour. As the several floors dissolve, this solution darkens. Changes to amber color. The mixture was cooled in a water bath and water (50 ml) was added at 25°C. Add gradually. This cloudy mixture was extracted with toluene (2 x 50ml) to obtain The resulting toluene phase was dried over sodium sulfate, filtered, and evaporated to dryness to give a glassy Get a solid. This solid was determined to be 8-chloro-3°4,5.6-tetho. lahydro-2,6-methano-2H-1-penzoxocine-10-carboxylic acid. Ru.

'H-NMR (CDCIs) δ: 10.2 (s, IH); 7.9 (d, IH); 7.2 (d, 18); 4.9 (m, IHj; 3.3 (a IH); 1.2-2.4 (m, 8H).

The compounds of the present invention can be readily obtained from non-toxic compounds by methods commonly utilized in the art. Can be converted to acid addition salts. The non-toxic salts of the present invention have an acid component that is Inorganic acids such as hydrochloric acid, odorous Hydrohydric acid, sulfuric acid, nitric acid and phosphoric acid and organic acids such as methanesulfonic acid, benzene sulfonic acid, acetic acid, propionic acid, maleic acid, succinic acid, glycolic acid, lactic acid , salicylic acid, benzoic acid, nicotinic acid, phthalic acid, stearic acid, oleic acid and salts prepared from etc.

Compounds within the scope of the invention have useful gastric prokinetie effects. It has antiemetic effect and poor receptor binding activity. These compounds themselves upper bowel motility and the reverse of the gastroesophageal It is valuable in the treatment of flow disorders.

Additionally, the compounds of the invention may be used to treat diseases associated with impaired motility of the gastrointestinal tract, such as delayed fasting. (retarded gastric eIoptying), indigestion, May also be useful in treating intestinal, esophageal reflux, peptic ulcers and emesis . Compounds within the scope of the invention exhibit 5-1f'rs antagonism and also treat mental disorders, For example, in the treatment of schizophrenia and anxiety, as well as in the prevention of migraines and cluster headaches. It is believed to be useful in treatment. The compounds of the present invention may contain mostly or It is selective in that it has no dopaminergic antagonistic activity.

The ability of the compounds of the invention to exhibit pharmacological responsiveness that can be correlated with activity in humans. Various animal tests can be performed to clarify the potency. these Tests include gastric motility, emesis, and ErHTs receptor selection for Formula V and shoulder compounds. factors such as selective antagonism and its effect on islet dopamine receptor binding properties. include.

The compounds of the invention exhibit significant activity when tested under the various conditions described above. That's what I found out.

One such test is “Rat Starvation: Amberlite Bead Method (Rat Starvation)”. Gastric EJfiptying: Al11berlite Bead Method) J. This test is performed as follows.

This study evaluates the effect of a test drug on chow starvation in rats It has been devised as follows. This procedure is 1. , E., Borella and Bitake Lippmann, Digestion, 1980.20 ．． This is an improvement on the procedure used in pp. 26-49.

soil! Amberlite™ beads in phenol red solution and let it soak in for several hours. Phenol red acts as an indicator and The color changes from yellow to purple as the bead's environment becomes more basic. This penetration After that, the beads were added to 0. Rinse with NaOH to make the beads purple, then Wash off the NaOH by washing with deionized water.

The beads were tested several times at 1.18 and 1,41! Filter through I11 sieve and remove these Obtain beads with a particle size range of . This process is carried out using large amounts of water. the beads Store in salt water until actual use.

Male Sprague-Dawley rats were treated with an arbitrary amount of Animals were fasted with water for 24 hours prior to this study. Randomize rats N=6 or divided into 7 treatment groups.

The test drug was prepared as a 0.5% methylcellulose solution and administered at 10 ml/kg. Administer to rats by oral route at a dose volume of 0.5% for control rats Methylcellulose is administered by oral route at a dosage volume of 10 ml/kg. throw One hour after administration, rats were given 60 Amberlite beads by intragastric route of administration. Ru. These beads are attached to a 16 gauge tubular adapter and a syringe. Discharge through a 3 inch PE205 tube. A small piece of PE50 tube Placed inside the tubular adapter to prevent backflow of the beads into the syringe. Applicable The beads are flushed into the stomach of each rat along with 1 ml of saline.

Thirty minutes after administration of the beads, the rats are sacrificed and their stomachs removed. remains in each stomach After washing the beads with NaOH, their number is counted.

Subtract the number of beads remaining in each stomach from 60 to obtain the number of beads eliminated.

For each treatment group, calculate the average number of beads ± S, E, L. from control The % change in is calculated as follows.

[(Average control group - Average drug test group/Average control group) X100 Statistical significance can be determined using a t-test on individual diets, with 0.0 A probability of 5 or less is considered significant. Compounds of the invention as antiemetics To demonstrate the ability of Cisplatin-induced emesis in ferrets (Ci splatin-1induced Emesis in the Ferret )” can be used. This test Han P, Florezhik (F lorezyk), J., E., Schurig & W., T. Brodner's Cancer Treatment Reporter Canc erTreatment Reports), 1982 (January), Vol. This is a modification of the paper published in , 66, No. l.

Cisplatin has been shown to induce vomiting in dogs and cats. Furore Zitsuku et al. demonstrated a similar effect using ferret.

procedure Castrated male Pitch ferrets weighing 1.0-1.5 kg. It has an insertion catheter placed in its jugular vein. After a recovery period of 2-3 days , begin the experimental procedure.

30 minutes before administering cisplatin, give ferrets a dose volume of 2.0 ml/kg. A compound of the invention in 0.9X saline is administered (intravenous route (i,v,)).

45 minutes after administration of cisplatin, the ferret was given a dose of 2.0 ml/dose again. A 0.9% saline mixture is administered (i, v,) in kg.

Cisplatin was administered by intravenous route (i, v,). Administer cisplatin lO■Ag at a dosage volume of 2.0 ml. give

The time point of administration of cisplatin is designated as time 0. Ferret was given for the experimental period (4 hours). Observe. The time elapsed until the first vomiting episode was recorded, and the vomiting period was also Also record the total number in between.

Vomiting (vomiting) episodes are associated with agitated behavior, such as restless pacing around the cage. Characterized by rows and rapid left and right movements. At the same time as this behavior, continuous Several retching movements were observed, followed by a single strong retching, followed by A person's retching may or may not involve vomiting of the stomach contents. continuous unit Immediately after the strong retching of -, the fly-left becomes calm. A single cough or Retching is not counted as a vomiting episode.

D-2 dopamine receptor binding assay This D-2 dopamine receptor binding assay Say is Ian Cresse, Robert Schneider (R bert 5chneider) & Solomon H, Schneider (Solamo n pressure 5chneider), Europe, J, Pharamcol,... 46:377-183 (1977) and slightly improved it. It was developed by Spiroperidol l) is a butyrophenone neuroleptic, which affects dopamine receptors in brain tissue. The affinity for Pta is greater than that of any other known drug. expensive. This is a highly specific receptor for dopamine (without cyclase binding). K value is 0.1-0.5 for D-2 inhibition and D-1 inhibition. 300 nM.

Sodium ions are important modulators of dopamine receptors. The D-21 nose The affinity for puta is significantly increased by the presence of millimolar concentrations of sodium chloride. I can't stand it. The Kd of 120- in the absence and presence of sodium chloride is respectively 1.2 and 0.086 nM. Standard conditions include sodium chloride (12 0 m) is present in all assays.

The caudate nucleus (striatum) is used as the receptor source. Because this is the brain and This is because it contains the highest concentration of dopamine receptors in the periphery.

Published Charles-River, weighing 250-300g Decapitate the rat, remove its brain, chill on ice, immediately dissect the caudate nucleus, and remove the brain. Cool on ice cream.

Tissues can be stored indefinitely at -70°C. For the assay, caudate nucleus Polytron homogenizer in 30 ml of Tris buffer (pH 7° 7.25°C) Homogenize using an icer. 40.000g of this homogenate (SS - Centrifugation for 15 minutes at 18,000-19,00 ORPM in a 340-meter Process. Resuspend the pellet in fresh buffer and centrifuge again.

Resuspend this final pellet in 150 volumes of assay buffer.

SOO μl of caudate nucleus homogenate, 50-μl of Tris buffer (pH at 35°C) 7,4), 5mM MgSO4, 2-EDTA-2NA, 120-NaCl , 0.1% ascorbic acid, 0.4 8H-spiroberidol and test Specific in a total reaction volume of 2 ml containing compound or abscess buffer 'H-spiroperidol binding is assayed.

In this assay, if catecholamines are present, 10 μl of bulk Phosphorus should be included in the reaction mixture to inhibit monoamine oxidase. be. The samples were incubated for 30 minutes at 37°C, then 5ml of ice-cold 5o Add rfM Tris (TRISX pH 7.7 at 25°C), Brandel Reeepter GF/B glass fiber filament on the Binding Filtration) device. Filter through a router. Wash the filter twice with 5 ml of Tris buffer each time. Wash. Assay groups were assayed in triplicate and treated with lμMd(+)butaclamol ( The amount of non-specific binding is measured using the following method (butaclaml). filter Place in a vial containing 10ml of Ecoscint phosphole. , shake for 30 minutes, and use a quench curve to drain the liquid. dpw+ is measured by body scintillation spectroscopy. Protein is biora Coomassie Blue G-250 stain from Bio-Rad was used to stain the brush. Bradford! t, Anal, Biocheu, 1976, 72. p.

Measured by the method of No. 248. As a protein standard, Bio-Rad (Bio-Rad) Bovine γ-globulin from Rad) is used.

Bezold-Jarisc in anesthetized rats h) Effect 1 administered via intraperitoneal (i, p,) route to male rats weighing 260-290 g; The animal is anesthetized with 25 g/kg-' urethane, and a cannula is inserted into the trachea. medicine Insert a cannula for intravenous injection (i, v,) into the jugular vein. in the left carotid artery Blood pressure is recorded by the cannula and input into a saline-filled blood pressure transducer.

Continuous heart rate measurements are obtained from the blood pressure measurement recording. This Besordo Giarrissi (Bezo 1d-Jar 1sch) effect is 5-stone on i, v, path induced by a rapid injection of porpus and a drop in heart rate is measured. each heartbeat In number, using the lowest dose of 5-HT that induces a clear drop in heart rate. , first set up an immutable response. 5-) Injections of rr are made every 12 minutes and test compound The dose-response curve of the 5-HT dose was gradually increased 5 minutes before each 5-HT injection. of the compound. This effect on 5-HT-induced bradycardia The effect of the compound on the bradycardia induced by 5-HT before injection of the compound as a percentage Calculate by

In another experiment to determine the 5-■ antagonism time produced by the compounds of the invention. Injected a single dose of the compound 5 minutes before administration of 5-)rr, then repeated injections. The effects of seven 5-1fT administrations were then followed. Besold Jarish The effect of the compound on the efferent vagal limb of the reflex is Test by electrically stimulating the tip. Unipolar electrical stimulation uses a pair of silver electrodes. 5 loads (straf ns) using a 1ais rectangular pulse. Pulse frequency is 5-30Hz The frequency-response curve can be varied with i, V, and Make it before and 10 minutes after.

The results of the above tests demonstrate that compounds within the scope of the invention have peripheral and central effects on the nervous system. diseases associated with impaired gastrointestinal motility, e.g. Treatment of starvation, indigestion, flatulence, esophageal reflux and peptic ulcers, as well as central nervous system It is suggested that it is useful in the treatment of thread disorders such as psychosis.

Compounds of the invention are suitable for the selected route of administration, e.g. oral or parenteral administration. It can be administered to mammalian hosts in a variety of forms. In this context, parenteral Administration may be by the following routes, such as intravenous administration, intramuscular administration, subcutaneous administration, or intraocular administration. , intraosseous administration, transepithelial administration including transepidermal administration, intraocular, sublingual and buccal administration. and topically for the eye, epidermis, bulbar, rectal and inhalation and aerosol Including nasal inhalation and rectal administration.

The active compounds of the invention may be present, for example, together with an inert diluent or with an assimilable edible carrier. The active compound can be administered orally with hard or soft gelatin shell capsules. or can be compressed into tablets or added to food in a therapeutic diet. Can be directly blended. For oral administration, the active compound can be formulated with excipients and possible tablets, buccal tablets, troches, capsules, elixirs, suspensions, It can be used as a syrup, aqueous agent, etc. Such compositions and formulations are It should contain at least 0.1% of active compound. The percentage in the composition and formulation The amount may, of course, vary and advantageously ranges from about 2 to about 6% of the weight of the unit dose. It can be within the range. The amount of active compound in such therapeutically useful compositions may vary depending on the appropriate The amount is such that the dose is obtained. The compositions and formulations of the clever invention can be administered orally. For oral administration, these tablets, troches, pills, capsules, etc. may also contain: You can That is, binders such as gum tragacanth, gum acacia, gum starch or gelling agents, excipients such as dicalcium phosphate, disintegrants such as lubricants such as corn starch, potato starch, alginic acid, etc. and sweeteners such as sucrose, lactose or saccharin Can also add flavorings such as peppermint, wintergreen oil or cherry flavor can do. When the dosage unit form is a capsule, the capsule is of the type described above. In addition to the above materials, a liquid carrier can be included. Various other materials exist as coatings. It is possible to improve the physical form of the dosage unit. for example , tablets, pills or capsules may be coated with shellac, sugar or both. Ru. Syrups or elixirs contain the active compound, sucrose as a sweetener. , methyl and propylparabens as preservatives, dyes and flavorings, e.g. May contain berry or orange flavor. Prepare any dosage unit form Any materials utilized in the should be non-toxic. Additionally, the active compounds may be formulated into sustained release formulations. Both are possible.

The active compounds can also be administered by the parenteral or intraperitoneal route. free salt Solutions of the active compound as a base or pharmaceutically acceptable salt may be prepared with a suitable surfactant. , for example, using water mixed with hydroxypropyl cellulose.

Dispersions also include glycerin, liquid polyethylene glycol, and mixtures thereof. It can also be prepared using oil. Normal storage and Under conditions of use, these formulations contain preservatives to inhibit microbial growth. include.

Dosage forms suitable for injectable use include sterile aqueous solutions or dispersions as well as sterile injectable water. sterile powders for the extemporaneous preparation of liquid solutions or dispersions. in all cases , the dosage form must be sterile and can be easily introduced into a syringe. It needs to be liquid to the extent that it can be used. It must be stable under manufacturing and storage conditions. It must also be preserved against the contaminating action of microorganisms such as bacteria and fungi. I have to be there. The carrier may be a solvent or dispersion medium, such as water, ethanol, etc. , polyols (e.g. glycerin, propylene glycol and liquid polyethylene) lene glycol, etc.), appropriate mixtures thereof, and edible oils. suitable In the case of a dispersion, fluidity can be improved by using a coating such as lecithin. It can be maintained by maintaining the diameter and by using surfactants. microorganisms The action is similar to that of various antibacterial and antifungal agents, such as parabens, chlorobutanol, It can be inhibited by phenol, sorbic acid, thimerosal, etc. in many cases It may also be preferable to include isotonic agents, such as sugars or sodium chloride. Applicable note If long-term absorption of the injectable composition is required, absorption delaying agents such as aluminum may be used. Monostearate and gelatin can be included.

Sterile injectable solutions contain a predetermined amount of the active compound, optionally containing various other ingredients enumerated above. It is prepared by blending in a suitable solvent and then sterile filtering.

Generally, dispersions may contain a variety of sterile active ingredients selected from those listed above. prepared from For sterile powders for preparing sterile injectable solutions, preferred The preparation methods are vacuum drying and freeze drying, and these techniques allow the active ingredient to be combined with the supernatant. a pre-sterilized and filtered solution containing any additional ingredients selected from: A powder containing the components is produced.

The therapeutic compounds of this invention can be administered only to mammals and include pharmaceutically acceptable compounds such as those described above. It can be administered in combination with a carrier, the proportions depending on the solubility and chemical properties of the compound. , determined by the chosen route of administration and standard pharmaceutical practice.

The physician will determine the dosage form and selected characteristics that are most appropriate for prevention and treatment. The treatments of the invention vary depending on the specific compound and the particular patient being treated. will determine the dosage of the drug. Doctors generally start treatment with low doses and If necessary, increase the dosage in small increments until the optimal effect under the circumstances is achieved. will try to do so. This therapeutic dose generally ranges from 0.1 to 20 mg, or about 0. O1 to about 50 ■/kg (body weight) for 7 days and more. However, 1 13+ may be administered in several different doses, from one to several times. For oral administration higher doses are required.

international search report PCT/Ro391106610 THXS XWTEmikTXONAL SR entered RCI! ING 0’T type O R Engineering τY CC0N5XD τ Ward Aτ τ0 ABOn-XDP2TXFXED 　XltTERMkTXOHkL　kPPTjCATXON　HiOFIJil　 190? COMPLY WI〒H1■ Ryo Soo nλ) As per τSOF σ, work y OF X1rn R T work ω is also good 10 8W■1Navy-1■Rike α-ko D1FORPJIC! !　X1r’lEMTXON ARI! :VL Input compound containing a carb egLia halida, classified In class562 ．． 5ubeLass 1140゜VX engineering, A co+mound conta ining an acyl fluorid* moiety, classi fied　1■ class 562,5ubclass 849゜X engineering L Sulfur-co taining carboxamide@s,clawifisd in c lams 5641 subcLass 162 (R” m) DIX).

Pσ10591106410 XV, Carboxallid@s whhar・branch n a b nz・n* ring is bonded dirge carbaryl, classifi@d in class 564. 5u bclass 1 floor.

XVL Multicyclic carboxamide@s, classif ied in class 564.　5ubclass171゜ XVIL AcyeLic 5urf mouth namid@s, classify d in class 5g4.5ubclass 99 (R”-HNX).

Continuation of front page (51) Int, C1,5 identification symbol Internal office reference number C07D 498108 8415-4C (72) Inventor: Stud William L. United States of America Pennsylvania 19438 Harleysville Store Road 611 (72) Inventor Powers Matthew Earle United States Pennsylvania state 19504 Bart R.D. 2 Box 260° I (72) Inventor Woodward Rick Gee - Praue State, United States 19808 Wilmington Lindell Boulevard 2108 (72) Inventor Gorek Frederick A. Pensilver, United States of America nia state 19066 Merion Station Baird Road 416 (72) Inventor Rodriguez Walter United States Pennsylvania 19518 Douglas Ville Mulberry Brace 208

Claims (1)

[Claims] 1. Polycyclic oxygen containing at least two chiral centers in fused or bridged ring positions A method for producing a substantially optically pure compound having a ring system, the method comprising: Together with cycloalkenyls having an orthochiral center, cycloalkenyls having an orthochiral center A method characterized by subjecting a loalkenyl substituent to acidic cyclization conditions that do not racemize it. . 2. The method of claim 1 comprising selective acidic conditions for the production of fused oxygen-containing ring systems. . 3. A method according to claim 1 comprising selective acidic conditions for the production of bridged oxygen-containing ring systems. . 4. from a cycloalkenylphenyl ether having a chiral center The method according to claim 1, for producing a cycloalkenylphenol having the following. 5. 2. A method according to claim 1, which produces a substantially optically pure compound of the formula: So, ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, one of A or B is CHR6, and the other A or B is a single bond; Y is CHR; n is 0, 1 or 2; R' is hydroxy, alkoxy, aralkoxy, halo, OM (M is alkali or alkaline earth metal), or NH-X, where X is hydrogen, alkyl , aralkyl, acyl, or Z, and Z has a mathematical formula, chemical formula, table, etc. ▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and its stereoisomers; R and R1 are independently hydrogen, alkyl, halo, alkoxy, aryl, aral Kyl, haloalkyl, amino, alkylamino, sulfonyl, alkylsulfa is mil or alkylsulfonyl; R2, R3, R4, R5 and R6 are independently hydrogen, alkyl, halo, alkoxy, aryl, aralkyl or haloalkyl and adjacent R2, R3, R4, R5 and R6 groups jointly form a double bond. You may. ) The compound represented by the formula below is mixed with trihaloacetic acid or trihaloacetic acid and sulfur. A method characterized in that it is treated with a mixture of acids and the compound obtained is isolated. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R■ is hydrogen. 6. The method according to claim 5 for producing a compound represented by the following formula. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ 7. The method according to claim 5 for producing a compound represented by the following formula. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ 8. The formula below: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ By treating the compound represented by sulfuric acid with sulfuric acid, the compound represented by the following formula is produced. 4. The method of claim 3 for manufacturing. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ 9. The formula below: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ Treating the compound represented by with trihaloacetic acid or a mixture of trihaloacetic acid and sulfuric acid The method according to claim 6 for producing a compound represented by the following formula. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ 10. The formula below: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R is hydrogen or halo, R1 is hydrogen, amino or mono- or dialkyl and R' is alkoxy). Treatment with acetic acid or a mixture of trifluoroacetic acid and sulfuric acid and hydrolysis of the resulting ester The method according to claim 9 for producing a compound represented by the following formula by Method. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R is hydrogen or halo, R1 is hydrogen, amino or mono- or dialkyl It's Ruamino. ) 11. The formula below: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ By treating the compound represented by with sulfuric acid or a mixture of sulfuric acid and trihaloacetic acid 4. The method according to claim 3, for producing a compound represented by the following formula. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ 12. The following formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is hydrogen or halo , R1 is hydrogen, amino or mono- or dialkylamino, and R' is Compounds represented by (alkoxy) sulfuric acid or a mixture of sulfuric acid and trifluoroacetic acid By treating the resulting ester with a substance and hydrolyzing the resulting ester, the following formula 12. A method according to claim 11 for producing a compound. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R is hydrogen or halo, R1 is hydrogen, amino or mono- or dialkyl It's Ruamino. ) 13. The formula below: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ Treating the compound represented by with trihaloacetic acid or a mixture of trihaloacetic acid and sulfuric acid The method according to claim 5 for producing a compound represented by the following formula. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, one of A or B is CHR6, the other A or B is a single bond, and Y is , CHR; n is 0, 1 or 2; R and R1 are independently hydrogen, alkyl, halo, alkoxy, aryl, ara Alkyl, haloalkyl, amino, alkylamino, sulfonyl, alkylsulf amyl or alkylsulfonyl; R2, R3, R4, R5 and R6 are Standing hydrogen, alkyl, halo, alkoxy, aryl, aralkyl or halo and the adjacent R2, R3, R4, R5 and R6 groups jointly form a double bond. may form; X is Z, and Z is ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Numbers There are formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, There are chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and its three-dimensional shape It is an isomer. R and R1 are independently hydrogen, alkyl, halo, alkoxy, aryl, aral Kyl, haloalkyl, amino, alkylamino, sulfonyl, alkylsulfa is mil or alkylsulfonyl; R2, R3, R4, R5 and R6 are independently hydrogen, alkyl, halo, alkoxy, aryl, aralkyl or haloalkyl and adjacent R2, R3, R4, R5 and R6 groups jointly form a double bond. You may. )14. The formula below: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ By treating the compound represented by with sulfuric acid or a mixture of sulfuric acid and trihaloacetic acid 9. The method according to claim 8, for producing a compound represented by the following formula. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, one of A or B is CHR■, the other A or B is a single bond; Y is , CHR; n is 0, 1 or 2; R and R1 are independently hydrogen, alkyl, halo, alkoxy, aryl, ara Alkyl, haloalkyl, amino, alkylamino, sulfonyl, alkylsulf amyl or alkylsulfonyl; R2, R3, R4, R5 and R6 are Standing hydrogen, alkyl, halo, alkoxy, aryl, aralkyl or halo and the adjacent R2, R3, R4, R5 and R6 groups jointly form a double bond. may form; X is Z, and Z is ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Numbers There are formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, There are chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and its three-dimensional shape It is an isomer. 15. The formula below: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R is hydrogen or halo, R1 is hydrogen, amino or mono- or dialkyl trifluoroacetic acid or trifluoroacetic acid By treatment with a mixture of fluoroacetic acid and sulfuric acid, the compound represented by the formula 14. The method according to claim 13 for producing. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ where R is hydrogen or halo and R1 is hydrogen, amino or mono- or dialkyl It is amino, and X is Z. 16. R is chloro, R1 is hydrogen, X is Z, and Z is ▲ mathematical formula, chemistry There are formulas, tables, etc.▼ and its stereoisomers; thus 2-chloro-[5a(S)-9a(S)( 5a,6,7,8,9,9a-hexahydro]dibenzofuran-4-[N-(1 - Contract for manufacturing azabicyclo[2,2,2]oct-3-yl)carboxamide The method according to claim 15. 17. The formula below: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R is hydrogen or halo, R1 is hydrogen, amino or mono- or dialkyl (X is Z) in sulfuric acid or trifluoroacetic acid. and sulfuric acid to produce the compound represented by the formula below. 15. The method according to claim 14. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ where R is hydrogen or halo and R1 is hydrogen, amino or mono- or dialkyl It is amino, and X is Z. 18. R is chloro, R1 is hydrogen, X is Z, and Z is ▲ mathematical formula, chemistry There are formulas, tables, etc.▼ and its stereoisomers; thus 8-chloro-[2(S)-6(R)-meta] Nor-2H-3,4,5,6-tetrahydro]-1-benzoxocine-10-(N -(1-azabicyclo[2,2,2]oct-3(S)-yl)carboxamide 16. The method according to claim 15. 19. A method for producing a compound represented by the formula below, including the following steps. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, one of A or B is CHR6, and the other A or B is a single bond; Y is CHR; n is 0, 1 or 2; R and R1 are independently hydrogen, alkyl, halo, alkoxy, aryl, ara Alkyl, haloalkyl, amino, alkylamino, sulfonyl, alkylsulf amyl or alkylsulfonyl; R2, R3, R4, R5 and R6 are Standing hydrogen, alkyl, halo, alkoxy, aryl, aralkyl or halo and adjacent groups may jointly form a double bond. ) A step of esterifying substituted or unsubstituted salicylic acid to obtain phenol. The phenol was dissolved in triphenylphosphine, diethyl azodicyl, and boxylate and pure chiral 2-cyclohexen-1-(S)-ol. process to obtain chiral phenol cyclohexenyl ether. This phenol cyclohexenyl ether is treated at high temperature to induce Claisen rearrangement. 3-(3'-cyclohexenyl)salicylate at the new stereocenter. The process of moving the property. 3-(3'-cyclohexenyl)salicylate is treated with acid to ring-close and create chiral [5a(S)-9a(S)-(5a,6,7,8,9,9a-hexahydro] Dibenzofuran-4-carboxylate and chiral [2(S)-6(R)-methane] Tano-2H-[3,4,5,6-tetrahydro]-1-benzoxocine-10- Process of obtaining carboxylates. This ester is hydrolyzed with aqueous base to give dibenzofuranic acid as a salt. A process for selectively isolating from the salts of xosinic acid. Each salt is treated with mineral acid or organic acid to form chiral dibenzofuranic acid (S,S) and chiral dibenzofuranic acid (S,S). A process for obtaining benzoxosinic acid (R,S). 20. 20. The ring closure is carried out by refluxing with trifluoroacetic acid. How to put it on. 21. Claims that ring closure is carried out by treatment with a mixture of trifluoroacetic acid and sulfuric acid The method according to item 19. 22. 20. The method according to claim 19, wherein the ring closure is carried out with sulfuric acid. 23. A compound selected from the following compound group. ▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼▲Mathematical formulas, There are chemical formulas, tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Y is CHR; n is 0, 1 or 2; R' is halo, OM (M is an alkali or alkaline earth metal), or NH -X, X is hydrogen, alkyl, acyl, or Z, and Z is ▲mathematical formula, chemical There are formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas, tables, etc. There are ▼ or ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ and its stereoisomers. ; R and R1 are independently hydrogen, alkyl, halo, alkoxy, aryl, aral Kyl, haloalkyl, amino, alkylamino, sulfonyl, alkylsulfa is mil or alkylsulfonyl; R2, R3, R4, R5 and R6 are independently hydrogen, alkyl, halo, alkoxy, aryl, aralkyl or haloalkyl at least one of R6 is hydrogen; adjacent R2, R3, R4, R The 5 and R6 groups may jointly form a double bond.