TW403744B - Piperidinyl compounds - Google Patents

Abstract

Novel piperidiny1 compounds of formula I in which X and Y are independently selected from hydrogen, and C1-6 alkoxy, R1 is a six-membered heteroary1 rings containing from 1or 2 nitrogen atoms, which may bear 1-2 substituents selected from a group of formula ReS(O)n, wherein Re is selected from hydrogen and C1-6 alky1 and n is 0, 1 or 2; wherein at least one of the substituents on the six-membered heteroary1 ring is a chiral sulfoxide of the formula C1-4 alky1SO and pharmaceutically acceptable salts thereof, are useful as dopamine antagonist and are particularly useful as antipsychotic agents in humans. The compounds may also be useful in other neurological and psychiatric disorders including schizophrenia. Processes for preparing the piperidiny1 compounds are also described as well as their use in medicine.

Description

Patent application No. 83106463 i々 锐 ai 焉 修 if alfalfa (April 84) a7 B7 issued ^ Description < 1) Qin 03144 X and R1 are a substituent, and n 'is a substituent to accept the compounds of the present invention K and medicated agent therapy are: anti-soothing treatment can be followed by Y is selected from hydrogen, halogen containing 1 or 2 nitrogen atoms is selected from the formula ReS (0) η 0, 1, or 2; It is a salt with optical rotation. Ming Geng provides the medicament group, and the dosage is acceptable as shown in the appendix of the example, and it is effective to deliver 糸 neurological agents. M is provided or treated or prevented. Salt. The 6-membered heterocyclic ring of the present invention and Cl-e oxygen, wherein R β is selected from one of at least 6-membered heteroaromatic hydroxyl groups, and its formula is "-4 alkyl S0, and its pharmacy upper group; Contains 2 compounds derived from hydrogen and Ci-e hydrazone, which contain succinate, and its / pharmaceuticals or excipients. The system cells are used to respond to their D1 and D2 polysexual or psychosexual menstrual disorders. The formula I compound is for treating the salts acceptable in formula I as defined above. This compound can be used in patients who are prescribed for the treatment of pamine antagonist activity, which is usually administered. The required medicament or its method of medicament is as follows (please read the precautions on the back before filling this page)-installed, printed by J Industrial Consumer Cooperative of Central Standards Bureau of Ministry of Economy ) A4 specification (210X297 public attack) 403744 V. Description of the invention () The invention was printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) This invention is aimed at the novel pipe Pyridyl compounds containing optically active submills and related compounds And production methods. This compound and its active ingredient-containing pharmaceutical compound can be used as dopamine antagonistic cocoons, and is especially suitable for human antipsychotic drugs. This compound can be used for other neurological and psychiatric disorders * including schizophrenia The present invention also includes a methanamidine compound containing racemic thallium which can be used as a D2 dopamine receptor antagonist. See EP A 0 533 3 44 A1. On the other hand, the present invention relates to a methane thallium compound. In the above, it is a pure optically sub-mirror compound or optical isomer * and a pharmaceutical composition containing the active ingredient *, wherein the compound is used as a D1 and D2 dopamine antagonist and a 5HT2 serotonin antagonist. It has an improved balance and a better ratio of D1 / D2 dopamine antagonists, which is expected to have better clinical effects on humans. This compound is also a serotonin 5HT2 antagonist. The present invention is also limited to optically active methane A novel synthetic method of rhenium subfiber, wherein this method utilizes multiple oxidation methods to selectively oxidize methane hydrazone sulfide to form a submicron phase-rich mixture, which can be passed through Pure or substantially pure methanesulfonium is obtained by further purification. In addition, the present invention is not limited to the use of a selective oxidizing stone with a mirror image to recirculate the racemic material or enrich the undesired methanine. The mirror image is purified by this to obtain a pure mirror image. The present invention is based on the novel methane anthracene hexahydropyridyl sulfide compound and its pharmaceutically acceptable salts, and the formula in the example The definition of each functional group of I is as follows: -4- The paper A degree applies the Chinese National Standard (CNS) A4 specification (210x297 mm) A7 B7 repair 8 £] | No. 6463 patent application statement amendment page ( June 1987) I "丨 丨 丨 _ lf V. Description of the Invention (8) 741 0 ° C. After a few hours, the solvent was removed and the solid was dried under high vacuum (room temperature, 10 pascal, 1 h). In this step, 1.25 g (86 4%) of a yellow solid main compound 'was obtained, which was of analytical purity by NMR analysis. iH NMR (CDC13, 250 MHz) 8.35 (dd, J = 1.6, 4.7 Hz, 1H), 7.58 (dd, J = 1.7, 7: 7 Hz, 1H), 7.22 (m, 4H), 6.95 (hi 5H) , 4.27 (s, 1H), 3.58 (s, 1H), 3.48 (s, 2H), 3.28 (q, J-7.3 Hz, 2H), 2.89 (m, 2H), 2.80 (ddd, J = 9.3, 14.9, 10.7 Ηε, 2H), 2.62 (d, J = 1.5 Hz, 2H), 2.12 (m, 4H), I.35 (t, J = 7.2 Hz, 3H) MS (Cl, CH4) m / z 443 (M + l, 100), 471 (M + 29, 16), 425 (25) The following examples are the best steps for preparing the main compound. Section D Example 3 (-)-1- (9, 10 -dihydro-9 , 10-methaneanthracene-9-ylmethyl) -4- (2-ethylarylene-3-¾succinyl) hexahydrospin-4-ol in nitrogen 'will dissolve in non-dried toluene Diethyl D-tartrate (2.10 moles) was cooled and dissolved and titanium tetraisopropoxide (1.06 moles) was added; 1- (9,10-dihydro-9,10-methane anthracene-9-ylmethyl)- 4- (2-ethylsulfan-3-pyridyl) hexahydropyridine-4-ol (1.0 moU) and t-butyl hydroperoxide (1.18 moles). After the reaction was allowed to proceed for 48 hours, a 2N NaOH solution was added; the solid T i 0 2 was removed by filtration, and the solvent was evaporated to obtain a preferred main mirror phase with a ratio of 8: 1 (65-70% yield). Recrystallization in MeCN yielded (-) mirror phase in 72% yield; nip 185-186 with a specific optical rotation of [α] -106 (1.0 in MeOH). -3 8-This paper size applies to Chinese National Standards (CMS > A4 size (2l0X 297_mm) (Please read the notes on the back before filling this page) -I. Order by the Central Bureau of Standards of the Ministry of Economic Affairs. Employee Consumer Cooperative Co., Ltd. Printed Patent Application No. 83106463 i々 锐 ai 焉 修 if alfalfa (April 1984) a7 B7 ^ Explanation < 1) Qin 03144 X and R1 are generation groups, and n 'is a substituent Acceptable compounds K and medicated agents are available. Anti-soothing treatments for Y can be selected from the group consisting of hydrogen, halogen containing 1 or 2 nitrogen atoms selected from the formula ReS (0) η 0,1 ， Or 2; Among them are salts with optically active ions. Ming Geng provides the medicament group, and the dosage is acceptable as shown in the appendix of the example, and it is effective to deliver 糸 neurological agents. M is provided or treated or prevented. Salt. The 6-membered heterocyclic ring of the present invention and Cl-e oxygen, wherein R β is selected from one of at least 6-membered heteroaromatic hydroxyl groups, and its formula is "-4 alkyl S0, and its pharmacy upper group; Contains 2 compounds derived from hydrogen and Ci-e hydrazone, which contain succinate, and its / pharmaceuticals or excipients. The system cells are used to respond to their D1 and D2 polysexual or psychosexual menstrual abnormalities. The formula I compound is for treating the salts acceptable in formula I as defined above. This compound can be used in patients who are prescribed for the treatment of pamine antagonist activity, which is usually administered. The required medicament or its method of medicament is as follows (please read the precautions on the back before filling this page)-installed, printed by J Industrial Consumer Cooperative of Central Standards Bureau of Ministry of Economy ) A4 size (210X297 public attack) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 403744 g 5. Description of the invention (3) An effective dose of a pharmaceutical composition containing the active ingredient as described in Formula I, and Accepted carriers or diluted noodles. The invention is more limited to humans Method for generating resistance by D1 and D2 dopamine receptors * It is the administration of an antipsychotic amount of a compound according to formula I or a cocoon composition thereof * which contains the compound of formula I as the active ingredient. Under this requirement, the terms "alkyl" and "Alkoxy" includes its linear and branched compounds, but it is known that single functional groups such as "propyl" or "propoxy" include straight and branched bonds such as "isopropyl" or " Isopropoxy is a special meaning. 0 The term "halo" means fluorine, chlorine, bromine, and iodine unless otherwise specified. The term "hydroxy" means its original meaning and includes the following items: And as a substituent. Ci-e alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, succinyl * t-butyl, pentyl, isopentyl * neopentyl , And isohexyl. C ^ -3 alkyl includes methyl, ethyl, and propyl. Ci-e alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy • neopentyloxy * hexyloxy and isohexyloxy. Ci-3 alkoxy includes methoxy * Ethoxy and propoxy. 5- and 6-aryl aromatic hydroxy heterocycles include 1-3 heteroatoms * selected from nitrogen, oxygen, and sulfur, including 2,3- and 4-pyridyl, 2-pyridyl, 2- and 4-pyrimidinyl, 3- and 4-pyridyl, 3, 4- and 5-isothiazolyl, 2- · 4- and 5-oxazolyl, 2-, 4 -And 5-thiazolyl, 4- and 5-oxadiazolyl, 2- and 3-furyl, 2-, 4- and 5-oxazolyl, and 2- and 3-thienyl. The above ring The form may optionally carry the substituents listed in the previous paragraph. 5- and 6- | (Please read the notes on the back before filling this page) MW * l. Order -Finl pr -6- This paper size Applicable to China National Standard (CNS) A4 specification (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 403744_b7 ____ 5. Description of the invention (~) Aromatic hydroxyl benzene derivative fluorene ring includes, various hydroxyfluorinyl groups , Isoborinyl, and benzothiazolyl, which may be substituted by the above-mentioned dentyl or Ci-e alkyl or alkoxy group (β-βhydroxyalkyl includes hydroxymethyl, hydroxyethyl, 2-hydroxy Ethyl, 1-3 via propyl, 1- via propyl, and 1-3 via butyl. X and Y include hydrogen and halogen. Ci-e alkyl includes Ci-4 alkyl, including methyl, ethyl, propyl, isopropyl, butyl * tert-butyl and isobutyl.

Ct-e alkyloxy (alkoxy) includes Ci-4 alkoxy, including methoxy, ethoxy, propoxy, isopropoxy, butoxy * isobutoxy and tert-butoxy base. 5- and 6- | aromatic hydroxyl heterocycles including 3 heteroatoms selected from nitrogen, oxygen, and sulfur, including 2,3- and 4-pyridyl, 3-, 4-, and 5-isothiazole Groups, 2-, 4-, and 5-thiazolyl groups, and 2- and 4-oxazolyl groups, among which the sulfonium may be optionally substituted with the above substituents. The benzene derivatives of 5- and 6-n-isoaromatic hydroxyl groups include 3-quinolinyl, 4-isohydroxyquinolinyl, 2-methoxy-3-quinolinyl, 2-benzothiazolyl, and 2-benzothienyl. Ci-e hydroxyalkyl includes Ci-a hydroxyalkyl, such as hydroxymethyl, 1 or 2 hydroxyethyl, 1-3 hydroxypropyl. Preferably, X and Y are hydrogen and chlorine, and M hydrogen is preferred. R1 is preferably an isoaromatic hydroxy ring of 6-¾, and is substituted by 2 substituents, preferably including 3-pysalyl, and at the 2-position M G-4 alkylsulfinic acid Substitution where Ci-4 alkylsulfinic group renders the preferred compound optically active. As shown in the following examples, preferred compounds can be selected from the formula I: X and Y are hydrogen; R1 is 3-pyridyl, substituted at the 2-position KC: i-4 alkylsulfinyl. -7- This paper size applies to Chinese National Standard (CNS) M specifications (210X297 mm) (Please read the precautions on the back before filling this page)-Binding. Order. 〇 Printed by the Central Consumers Bureau of the Ministry of Economy 403744_Βτ _______ 5. Description of the invention (5) A better compound is (-)-1- (9,10-dihydro-9,10-methanefluoren-2-methyl) -4- (2-ethylsulfinic acid) Methyl-3-pyridyl) hexahydropyridin-4-ol. The present invention also includes mirror image mixtures of the above-mentioned preferred compounds. Among them, (-) mirror images are more than (+) mirror images. Generally speaking, when X is gas and Y is hydrogen, the stereochemistry of 9S, 10S is better. Stereochemistry can be determined by standard methods. For example, at the 9-position on the methane ring, M chloride and optically active resolving agent are coupled to obtain a mixture of diastereomers, which can be recrystallized or a high performance liquid layer. Analytical method (" 1 ^ 1 ^ "> or other chromatographic analysis method K can obtain pure diastereomers, and the stereochemistry of its crocodile pair can be determined by methods. Diastereomers, in a certain In some cases, it can be separated by partial crystallization. The compounds of the present invention can be selectively produced by the sulfide M optical oxidation method on the described heteroaromatic hydroxyl ring. Selective oxidation of sulfides The method can produce a mixture rich in mirror phase. Among them, the main mirror phase can reduce the unnecessary sulfinate mirror phase and re-oxidize K to produce another desired product through a recycling process. Generally speaking, the compound of formula I can be obtained by the described synthesis method. The alkyl sulfide portion can be prepared before the racemic oxidation and / or recycling steps. The compound of formula I is prepared as follows: (a ) The piperidine hydrazone having formula II and the corresponding compound such as PLi, In solvents, such as THF reaction. Lithium compounds can be produced by the reaction of formula PZ, where Z is halo or is hydrogen, and PZ is reacted with a Ca-e alkyl lithium compound, such as n-butyl lithium, the reaction temperature is -20 to -100 t; the produced compound, K isoaromatic hydroxyanion and 4-piperidone methane -8 ~ This paper size applies Chinese National Standard (CNS) A4 specification (210X2S »7 mm) (Please read the notes on the back before filling this page :)

-'tT .D. 403744 Α7 Β7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention u) After coupling, this is preferably used as an intermediate product (羼 in some inventions) * It is further modified to generate Formula I, in which the Ci-4 alkylsulfide is partially basicized (forming a female chick) * and reacted with a leaving group on a 5 and / or 6-ring heterocyclic ring, wherein the obtained methane-alkylsulfide intermediate product (Part of the present invention) will undergo specular phase selective oxidation; α) will react the corresponding amines of formula Ila with a suitable activator, such as lithium aluminum hydride or borane dimethyl sulfide (C) reacting an aldehyde of formula III (G is hydrogen) with pyridine relative to formula IV in the presence of a priming agent, for example, cyanohydrin; (¢ 0 a compound of formula I, wherein Ci-e alkoxy Both the base pair X and Y are required * will correspond to the compound of formula I, where X or Y is a hydroxyl group • reacts with a fluorenyl group and an alkyl halide to form an alkoxy compound. The compound M generated in the above steps is selected with a mirror phase Oxidizing agent with a mirror-selective oxidation effect, M generating formula I with optical rotation, and the present invention further provides preparation formula I A method of a compound and a pharmaceutically acceptable salt thereof, comprising oxidizing a compound of formula I, wherein X and Υ are as defined above * and R1 is as defined above, except that the formula Ci-4 is an alkyl group of formula Ci-4 S, which undergoes an optically active oxidation step to selectively oxidize the mirror phase of the formula "-4 alkyl S is the optically active yar of formula Ct-4 alkyl SO, and M generates a compound of formula I; if its agent is needed It is an acceptable salt that reacts a compound of formula I with an acid which can generate a physiologically acceptable anion or base and react with a physiologically acceptable cation. In general, it is preferred that a suitable oxidant be oxidized. Reaction, which includes (as above), for example, titanium / tartrate / peroxide mixture, -9-this paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) (please read the precautions on the back first) (Fill in this page)-Binding and printing. Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 403744. 5. Description of the invention (7) Such as titanium alkoxides (eg. Titanium tetraisopropoxide), dialkyl tartrate (eg . Diethyl tartrate) and alkyl hydrogenation Oxides (eg. Tert-butyl hydrogen peroxide). Other suitable oxidants include, optically active oxaziri.dine, such as (S)-(+)-camphoryl oxaziri.dine, and suitable enzymes. The reaction is usually It is carried out in an inert hydrocarbon solvent, such as methylbenzyl, and under cooling, eg. At -78t: to normal temperature. Preferably, the present invention is limited to a method for producing a compound of formula I (such as the first appendix after the example). (Shown on page), where X, Y and R1 are defined as follows: X and Υ are selected from hydrogen, halogen and Ca-e alkoxy, respectively; R1 _ _ from: 5-and 6- | isoaromatic hydroxy ring, It contains three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and its benzene derivative with a 1-2 fluorene substituent, selected from Ci-e alkyl, hydroxyl, and Ci-e alkoxy Group, which bears trifluoromethyl, h-β alkoxycarbonyl, Ci-e hydroxyalkyl, benzyloxy, halo, "-3 alkylaminocarbonyl" -3 alkyl * aminocarbonyl, Its formula is COHR ^ Rd, where "" and 卩 * 1 are respectively selected from argon, 2-pyrrolidinyl, and Ci-e alkyl, or where 1 and Rd together with its adjacent nitrogen atom form a 5- or 6-fluorene ring, where The nitrogen is the only heterogen , ReS (0) ", RfNH, and R * S, and wherein 1 ^

Rf is selected from hydrogen and “-βalkyl and η is 0 * 1, or 2 and R * is selected from

Ci-3 alkylcarbonylaminobenzyl and di (Ci-3) alkylamino (Ci-e) alkyl, wherein substituents on the 5- or / and 6- | One is an optically active submill, the formula of which is G-4 alkyl SO; this step includes: (a) generating 9-methynyl-9,10-dihydro-9,10 methane anthracene of the formula 2L2_, which is React the tricyclic aldehyde of formula UL with vinyl ester, where the ester is vinyl-10- This paper size is applicable to China National Standard (CNS) 8-4 specification (210X297 mm) (Please read the precautions on the back before filling (This page) • Binding. Order 403744 V. Description of the invention (8) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -0 (CO) (Ci-4) Alkyl M ethane-formaldehyde or acetaldehyde It is equal to Ca-4 alkylcarbonyloxyaldehyde, and its M is selected from the oxidized surface of Cr03 / H2S04M, acetone or similar oxidized cocoon or system reaction. M generates 9-carboxylic acid, such as formula L5_ * Or the corresponding alkylcarbonyloxyacid, which is then reacted with a diaryl phosphonophosphonium azide and trialkylamine in a suitable solvent, such as methyl isobutylphosphonium or the like, M Generate the corresponding glycosyl (or ^ -4Alkylcarbonyloxy > Azide is the main intermediate product, which is heated in ΙΙΚΚ or its equivalent solvent to generate the corresponding intermediate isocyanate, which is in excess of sodium hydroxide aqueous solution ( Reflux) or its equivalent test and HC1 aqueous solution (heating) or its equivalent acid reaction to generate amine-based enzymes (such as HC1 or a suitable salt) UL, which will be ring-contracted in the cation carbon ion, diazotization Step or its equivalent) M to form methyl fluorenyl-methane anthracene In addition, and less preferably, 9-carboxylic acid hydrazone or its equivalent MSCU * DMF is reacted in toluene, M to generate an intermediate acid halide, which It reacts with NaN3 (1.5 eq) to produce intermediate products and the corresponding nitrogen compounds, which are then heated to produce a separable cyanate salt. * After its alkalization, it generates an amine fermentation 2Ld (isolated from toluene or an equivalent solvent). Get free amines); in addition, acetic acid / HC1 mixture in tinctures, such as methylbenzyl or its equivalent, hydrolyze the intermediate product isocyanate to form a primary amine. The intermediate product undergoes ring contraction M to generate (b) The 4-piperidone is reacted to generate 4-piperidone of formula II, wherein the protecting group is selected from acetal or a known keto protecting group, and then reacted with a kanogen to reduce the intermediate 9-yl methanol. It is 9-ylmethyl * Μ to obtain the intermediate product and protected U, which is then protected by a suitable acid -11- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) m · nt ^ — Γ amml an \ ΎΙ n i- In {Please read the notes on the back before filling in this page) Order. 〇 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs i〇3744 V. Invention Description (9) won II; (c) Formation of intermediate isoaromatic hydroxyl hydrazones of formula I, which are selected from 5_ and 6-isoisoaromatic hydroxyls, oxygen * and sulfur, and their benzenes are derived from "-βalkyl, hydroxyl vg Cl-β" oxygen Carbonyl group, Cl-e "-3 alkylaminocarbonyl group Ci-3 * where Re & RdA is selected from P and Rd and its adjacent nitrogen atom is the only heteroatom Rf * selected from hydrogen and Re Is selected from Ci-a alkylcarbonylamine (Ca-e) alkyl, in which at least one substituent is suitably substituted; (d) to form the middle of formula I, and "-4 alkyl sulfur, Where 5- / Or 6- | is -S (Cl-4fluorenyl); (e) reverse the selective oxidant of the phase produced in step (d) to the A7 B7 product produced in the above step from: the base ring contains organisms, which -β 焼 oxyhydroxyalkylalkyl, amine hydrogen, 2-pyridine co-production ♦ ReS (0) C 1-β 焼 phenylbenzyl, 5- and / or leaving group, product, which replaces the chick Heteroaromatic compounds should produce better compounds, in which R1 is equal to 5- and / or 6-ring and 3 heteroatoms carry 2 atoms, which may carry tri-, phenylmethyloxycarbonyl groups, Its formula is pyridinyl, and it becomes 5-or 6 -i hetero », RrHH, and η is 0, 1 and bis (Ci-3) alkane 6- |, heteroaromatic. It can be burned by Cl-4. From azo, its fluoromethyl, halo, is CONReRd-6 alkyl or its ring, where the ReS, or, and 2 and the amino amino hydroxyl ring to the heterosulfur nucleophile The hydroxyl group of the group I is removed as described above to form a compound of formula I. At least one of the substituents of the hydroxyl ring is compatible with the compound of formula I under suitable conditions. Compound * and the tincture composition which can be used in the present invention are (-)-: 1- (9,10-dihydro-9,10-methanefluorene-9-yl-methyl 12- (Please read the Please fill in this page again for the matters needing attention)-Install. Order sl · I.ilillg. 5 * || | = _ .- -In This paper size is applicable to China National Standards (CNS> A4 size (210X297mm) Central Standard of Ministry of Economy Printed by 403744 A1 _ B7 of the Bureau's Consumer Cooperatives. V. Description of the invention (10)) Crystalline state of 4--2-ethylsulfinyl-3-pyridyl) piperidine-4-enzyme. Its preferred crystalline state is its melting point of 185-186 t: and its optical rotation coefficient is [a] -106. (C = 1.0 in MeOH). The above-mentioned preferred mirrors are extremely suitable for antipsychotic use. Use compound (-)-1- (9,10-dihydro-9, 10-methane anthracene-9-ylmethyl) -4-2-ethyl-pyridyl-3-salyl) piperidine The crystals of 4-ol are useful in the scope of the present invention for the treatment of psychosis in human patients. This part is characterized by the fact that the crystalline compound is an antagonist of the D1 / D2 dopamine receptor and the 5HT2 serotonin receptor. Since the antipsychotic effect can be achieved and the side effects caused by D2 receptor antagonism can be reduced, this state of equilibrium can be expected to achieve clinical utility. Production of crystalline (-)-1- (9,10-dihydro-9,10-methanefluorene-9-ylmethyl) -4-2-ethyl-sulfinyl-3-pyridyl) piperidine The preferred step of -4-fermentation is a feature of the present invention and includes: (a) Formation of a compound selected from 9-formamyl-9,10-dihydro-9,10-methane, will be in Scheme I The table shows 1A tricyclic aldehyde (X and Y = H) and vinyl acetate (> 1 eq), reacted in a closed test tube, the temperature of which is 180 t :, ethane generates ethane hydrazone of formula, and then Μ Jones reagent reaction (Jones reagent Cr03 / H2S04), which is dissolved in H20 / acetic acid. K is generated corresponding to 9-carboxylic acid 15_, which is in turn reacted with diphenylphosphonosyl-nitrogen (> 1 Eq) And triethylamine dissolved in methyl isobutyl blue is reacted in> 8010 to produce the corresponding acetazide, which is then heated in ΙΒΚ or its equivalent solvent to produce the corresponding intermediate isocyanate. Salt, the amount of sodium hydroxide aqueous solution (reflux) or its equivalent base and HC1 aqueous solution (heated) or its equivalent acid react with each other to form an amino alcohol, the table is 2JL (X and Υ = Η), and Can be separated into HC1 (Please read the precautions on the back before filling out this page) — 1 -Packing · -9 β-line-13- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 403 * 744 _ ;; _ 5. Description of the invention (u) salt, which passes through the middle of the young carbon The carrier (by diazotizing Na2N02 / H0Ac in H20) is used to shrink the ring to form 2_2_ (X and Y = H); In addition, the acetic acid / HC1 mixture acidifies the intermediate isocyanate in a solvent. This solvent It can be methylbenzyl to generate amine-based enzyme, which then undergoes ring contraction M by masculin intermediate product to form 2_2_; (b) produces formula 11 4 -piperidine_ (X and Y = Η), and formula 2J2_ The compound is reacted with a protected 4-piperidone, wherein the protected group is selected from acetaldehyde, which is then reacted with a boronogen selected from a polar solvent to produce a protected compound of formula II, and then M is appropriate. Deprotection of the K to form II; (c) to produce an intermediate compound of formula I, wherein R1 is 2-fluoro-3-pyridyl, and the compound of formula II is reacted with an anion formed from 2-fluoropyridine and LDA «(d) An intermediate product compound of formula I is formed, wherein R1 is 2-ethylthio-3-pyridyl, and EtSH is reacted with sodium hydroxide or a suitable Sickle in a suitable solvent. It is selected from 1-methylpyrrolidine _ or its equivalent, and the sulfur salt anion generated by it is reacted with the compound produced in step (c) above; and printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the note on the back first) Please fill in this page again for the matters) (e) Add the 1- (9,10-dihydro-9,10-methane 葸 -9-ylmethyl) -4- (2-ethylthio- 3-Pyridyl) piperidin-4-one reacts with diethyl D-tartrate in a cooling solution of non-dried methylbenzyl or its equivalent solvent; titanium tetraisopropoxide and tert-butyl hydroperoxide The product is a mixture of ethylsulfinylfluorenyl groups which is rich in mirror phase, which is recrystallized in a suitable solvent, such as MeCN or an equivalent solvent, to obtain a pure (-) mirror phase. Therefore, the present invention further provides (-)-1- (9,10-dihydro-9,10-methanefluorene-9-ylmethyl) -4- (2-ethylsulfinamilide-3-pyridine) The base paper size of piperidine-4-ol is applicable to the Chinese National Standard (CNS) A4 specification (210X297 gigabytes) 403744 Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Buyers and Consumers Cooperatives 5. Description of the invention (12) Crystals, It includes combining this compound (9, 10-dihydro-9,10-methanefluorene-9-yl-methyl) -4- (2-ethylthio-3-pyridyl) piperidine-4-ol with Diethyl D-tartrate (preferably cold), which reacts in a solution of methylbenzyl (preferably non-drying) or an equivalent solvent thereof; titanium tetraisopropoxide and tert-butyl oxide peroxide M A mirror-enriched ethylsulfinylfluorenyl mixture is formed, which is preferably recrystallized in a suitable solvent such as MeCH or its equivalent to obtain a pure (-) mirror-like object. If not available, it will be required The starting materials such as the above compounds can be produced by quasi-organic chemical synthesis techniques, or analogs can be produced by known methods for synthesizing chemical sequences. For example, a compound of formula R1Z can be used in the following phase Technology for It is Brandsma et al., Preparative Polar Organometa 1 1 ic Chemistry I, Springer-Verlag (1987). The following are the standard chemical abbreviations and initials. For example, Et is ethyl, THF is tetrahydrofuran, and lu is terbutin Group, RT is room temperature * DMS0 is dimethyl methylene, Me is methyl group, bz is carbobenzyloxy group and Ph is benzyl group. When it is Grignard test or alkyl lithium compound, Z is halogen Group, such as chlorine. According to the present invention, the commonly used intermediates as compounds are acids (G is a hydroxyl group) or hafnium halide of formula III (G is a halogen, such as chlorine). As the intermediate product shown in Scheme 1, it can be The following examples are described. The anthraquinone of formula 10 can be converted to the corresponding formula 12 by using zinc and ammonia water. The anthraquinone of formula 10 can be converted to the corresponding one by using phosphorus phosphonium chloride and N-methylformamidobenzene. 9-aldehyde. The reaction of aldehyde 14 with vinyl acetic acid (Diels Alder) can give a chain bridge compound 16 * which is oxidized in the presence of sulfuric acid (in the presence of sulfuric acid) to obtain the corresponding acid 18. Acid 18 and dimethyl dichloride (please (Please read the precautions on the back before filling this page). Binding. Order IIMIΙΙ · 1Ι-- 〇 The paper size is applicable National Standard (CNS) A4 specification (210X297 mm) 403744 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (13) Thallium telluride (for example, in Jiabenzhong) responds to 9-chloro The hydrazone is reacted with sodium azide (for example, in a mixed solution of water and propyl) to obtain the corresponding 9-fluorene chloride, and then mixed with sodium azide (for example, a mixed solution of water and propylene). Middle) reaction, the corresponding 9-fluorenyl azide is obtained, and after heating (for example, methylbenzyl), the corresponding hydrazone salt can be effectively reconstituted, and then the alkali hydrazone hydroxide After the reaction (in an alcohol, such as ethanol), the ethyl group is cut into hydroxyl groups, and then the isocyanate is hydrolyzed to an amine group to obtain amine 20. Then, from the reaction of the gold nitrate with amine 20 (for example, sodium nitrite dissolved in gallic acid), the ring is contracted to obtain 9-aldehyde of formula 22. In the presence of sulfuric acid, aldehyde 22 can be oxidized with K 3 O 3 to obtain the corresponding acid of formula 24 (corresponding to the acid of formula III, where G is a hydroxyl group). The corresponding 9-halogenated hafnium *, such as hafnium chloride, can be obtained by reacting acid 23 with thionine dihalide (thionium dichloride) or ethylene dihalide (thionium dichloride). The 2,7-dihalogenated substituted methane hydrazone can be prepared according to the following procedure. Unresolved acid 24, (if optically rich product is desired, M is resolved acid 24) its M-halo substituent at the 2-position is mono-substituted *, and then reacted with dithionyl halide to obtain a phase Corresponding 9-chlorinated brew. It can be reacted with a lower alcohol such as formazan or ethanol to obtain 9-fluorenyl ester. This 2-haloester can be nitrated at the 7-position using a suitable nitrating agent such as a mixture of trifluoroacetic anhydride and ammonium acetate under inert gas (such as nitrogen). This reaction will produce a 2-halo, 6 or 7-nitro isomer mixture, which can then be separated by conventional separation techniques. Appropriate migration reagents such as tin chloride can be used to convert the 2-halo-7-nitro isomer to the corresponding 7-amino-2-halo compound, which can be further diazotized. , Such as tert-butyl nitrite, and then converted to the corresponding -16 by copper chloride halide reaction. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling (This page) Installation.-Order 0-A7 A7 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 403744 --- 5. Description of the Invention (Partner) 2,7-dihaloalkyl ester. A suitable base (such as an alkali metal hydroxide) removes the ester, and M gives a corresponding 2,7-dihalo substituted acid. If methane radicals need to be replaced by oxidation (eg. 2-halo-7alkoxy), they can be prepared from the above 7-amino-2-halo compounds. Diazotizing reagents, such as tert-butyl nitrite, are reacted with the amine, and then reacted with a suitable acid to form a salt, such as trifluoroacetic acid (eg, with potassium carbonate in a trifluoroacetic acid solvent). The obtained trifluoroacetate can be hydrolyzed by a conventional method and reacted with a base in the presence of the corresponding Ca-e alkyl halide to link the Ca-e alkyl group with oxygen. The hydrazone chloride of formula III (G is halo) and hexahydropyridine of formula IV are reacted in the presence of a base, such as a trialkylamine, such as triethylamine, to form amine of formula Ila. As shown in Scheme 2, a suitable oxidant can be used to oxidize the corresponding formula 32 via hexahydropyridine to form piperidone of formula II. This oxidant can be (1 > chromium trioxide in the presence of sulfuric acid and use a suitable Solvents, such as acetone; (2) Trioxosulfide-pyridine complexes in the presence of bases, such as trialkylamine (eg, triethylamine), and use of suitable solvents, such as diazomethane and sister of DMS0 Or (3) a combination of ethylenedichloride and DMS0, followed by a K base, such as trialkylamine, and using a solvent, such as dichloromethane. The hydroxyhexahydropyridine of formula 32 can be selected from any of Scheme 2 The pathway is achieved. 9-aldehyde 22 can be directly reacted with 4-hydroxyhexahydropyridine and cyanohydrosulfana to obtain the corresponding amine 32. In addition, 9-aldehyde 22 can be first oxidized and converted into the corresponding 9 -Ammonia, and then react with the amount of 4-hydroxyhexahydropyridine, or react with the addition of a base, such as trialkylamine (for example, triethylamine), to obtain the corresponding amidine 30. W LAH in diethyl ether or In THF, hydrazine 30 can be used to obtain hydroxyhexahydropyridine 32. -17- This paper is compatible with Chinese National Standards (CNS) 8.4 square (210 × 297) PCT) (Please read the notes on the back of this page and then fill in) - stapling.

I --.-. L .-- gll II ο Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 403744 B7 V. Description of the invention (15) Hexahydropyridine of formula IV can be synthesized as shown in scheme 3. 4 -Hydroxyhexahydropyridine is reacted with a carbamoyloxy group (Cbz-Cl) or other suitable protecting group in the presence of a base such as Et3N * to protect the nitrogen atom of hexahydropyridyl and obtain M obtained the corresponding 1- (carbonated benzyloxy) hexahydropyridin-4-ol 52. Hexahydropyridin-4-ol 52 was oxidized with ethylene dinitrogen and DMS0, and then the M base was reacted with it in a solvent, such as dichloromethane, to produce the corresponding protected 4-piperidone 54. The organolithium compound PLi and piperidinone 54 are used to react, wherein R1 is as defined above, or Grignard reagent RlgZ, the reaction temperature is -20 to -70¾, which is reacted in a solvent * such as THF or diethyl ether, M Obtain the corresponding hexahydropyridine 56. Using a platinum catalyst on carbon (eg, 10% Pd / C) and cyclohexane in a solvent * such as acetic acid, 56 deprotection group can be obtained to obtain hydroxyhexahydropyridine of formula IV, all the above mentioned items Chemical synthesis materials are available and reported in the synthesis literature. According to the basic steps described below, K can be used to prepare the alkyl sulfur derivative of the present invention as the preferred optically active submill precursor. In solution * such as 1- (9,10-dihydro-9,10-methanefluorene-9-yl-methyl) -4- (2-fluoro-3-pyridyl) hexahydropyridin-4-ol ( It is prepared by reacting 2-fluoropyridine anions with 1 ~ (9,10-dihydro-9,10-methane-fluoren-9-ylmethyl) -4-piperidone and lithium bromide in a suitable solvent. , Such as THF, and the sodium salt of alkylsulfide compound (^ -4), which will replace the fluoro group. Under standard conditions, CU- * alkylsulfide compounds and sodium hydride are used to prepare sodium alkylsulfide. The reaction of the sulfide salt with the 2-fluoro derivative is refluxed for at least 3 hours, and then the water is used to slow the reaction. The aqueous phase is extracted with diethyl ether or other suitable organic solvents, and the resulting product is purified by a suitable chromatography method. Such as rapid chromatography, the size of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) (please read the precautions on the back before filling this page)-installed. V. Line 403744 Central Bureau of Standards, Ministry of Economic Affairs Printed by Employee Consumption Cooperatives V. Description of the invention (16) 1- (9, 10-dihydro-9,10-methane anthracene-9-ylmethyl) -4- (2-(^-4alkylthio-3 -Pyridyl > hexahydropyridine-4-ferment compound. The preferred compound obtained by this method is a 2-ethylsulfur derivative. A suitable fluorine-substituted heteroaromatic hydroxyl group as described above is reacted with an alkyl sulfide salt as the optically active precursor of the present invention. The above-mentioned 2-ethylthio derivatives or other Ci-4 alkylthio derivatives • Can be selectively and oxidized by the mirror phase to form the required and biologically active polyB amine receptor antagonists ◊ The above alkylthio compounds The selective oxidation step is as follows. In a cooled (-)-diethyl tartrate solution (-20t: >), it is dissolved in a suitable solvent, such as dry (anhydrous) methylbenzyl, and in Reaction in nitrogen * and dropwise addition of human tetraisopropoxide titanate. After stirring it for 5 minutes, add some alkyl sulfur derivatives * such as (9,10-dihydro-9,10-methane 葸 -9 -Methyl) -4- (2-ethylthio-3-pyridyl) hexahydropyridine-4-ferment. After maintaining the reaction at the above temperature for 25 minutes, cool to -78t !, and then add it with a syringe. Fresh and dry tert-butyl hydroperoxide (slight excess molar number). Increase the temperature to -15¾ for several hours (about 3 hours), and then put it in the 15¾ refrigerator without mixing. 18 hours. Add sodium hydroxide aqueous solution (approximately 1N) to slow down the reaction. Dilute the suspension with methylene chloride and filter through diatomaceous earth. After that, purify the product by chromatography. Mirror phase mixture of optical quotient rhyme wherein the ratio of the mirror phase is about 1: 3.7: (+) (^-4 alkylsulfinylmethanesulfonyl compound ratio (-) Ci-4 alkylsulfinyl ammonium Methyl methane-based compound (determined by HPLC analysis of the mirror phase). The product mixture is recrystallized in a suitable solvent, such as thermal methylbenzene, so that the ratio of the mirror phase mixture is 1: 99 * where ( -) Mirrors are the main products. Make it recrystallize, make pure -19- This paper size applies Chinese national standard, (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry 403744 V. Description of the invention () (-)-The mirror image is a crystalline solid. Scheme 4 describes the specific optical oxidation K of pyridylethylsulfide or isoaromatic hydroxy (het) CU-4 alkylsulfide compounds to form the respective sulfenyl pickling compounds. * He t in Scheme 4 represents 5- and 6-f heteroaromatic hydroxyl rings, as defined by R1 above. The preferred mirror image produced by this method is (-)-1- (9,10-dihydro-9,10-methanefluorene-9-ylmethyl) -4- (2-ethylsulfinamilide) -3-pyridyl) hexahydropyridin-4-ol. The present invention relates to a method for producing an optically active sulfinylmethanesulfonyl compound, which comprises (a) a compound of formula I, wherein X, Y and R1 are as defined, except that R1 includes Ca-4 sulfenyl sulfur * Reacts with (b), which is an asymmetric oxidant, which is selected from (1) titanium / tartrate / oxide, or (2) optical oxaziridine. * Its reaction is mirror-like, and M produces optical activity of formula I. Spectral oxide mixture. The present invention relates to the method of each of the above steps plus recrystallization to obtain a pure sulfinylfluorenyl mirror phase of formula I. The present invention also includes diastereomers in which at least one heteroaromatic hydroxyl substituent is an optically active sulfinyl sulfenyl group and the other optically active substituent is as defined above in an isoaromatic hydroxyl group or in a methane anthracene core . The steps of the present invention can produce an excessive amount of mirror phase objects. Therefore, the present invention is a novel method for generating a methanesulfonyl Yacron I mirror phase object. In Pitchen et al. J. Am.

Chem. Soc. 1984, 106, 8188-8193 describes the asymmetric oxidation of aromatic hydroxy-alkyl sulfide M by M-determined formulas to make amidine. The method of oxaziridine is described in D a ν i s e t a 1., J. A m. C h e m. S oc. 1 982, 10 4 5412. The present invention is directed to the oxidation of optically active sulfides of formamidine alkyl sulfide complexes. Other optically active oxidation methods that can be used under appropriate conditions include the enzyme method (M atmosphere peroxy-20- This paper is sized to the Chinese National Standard (CNS) A4 specification (210X297 mm) • —LI i * 11 · HI — > ϋ > L m J— '\: (Please read the notes on the back before filling out this page) Order the 403U4 A7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs _________ ΒΤ ___ 5. Description of the invention (ΐδ) enzyme In the presence of bovine serum albumin, M-oxidation was performed. The ratio of the mirror phase can be different according to different isoaromatic hydroxyl groups. The present invention is based on the step of converting the undesired submilled sulphonate into a sulfide, which is further subjected to mirror-selective oxidation to produce a better mirror or diastereomer. For example, compounds such as (a) 1- (9,10-dihydro-9,10-methane-9-ylmethylalkylsulfan-3-isoaromatic hydroxyl) hexahydropyridine-4-enzyme derivatives Its synthesis can be obtained from the corresponding G-4 fluorenylsulfinyl-3-isoaromatic hydroxy derivative by using a suitable kangen agent * such as zinc powder / tetrafluoroethylene. The preferred compound to be recycled by this method is a racemic compound or contains (+)-1- (9,10-dihydro-9,10-methanefluorene-9-ylmethyl) -4- (2-ethyl Sulfinylpyridinyl-3-pyridinyl) hexahydropyridine-4-enzyme, which has undergone derivation * to obtain (9, 10) -dihydro-9,10-methanefluorene-9-ylmethyl) 4- (Ethylthio-3-pyridyl) hexahydropyridine-4-ferment. As mentioned, this compound is then mirror-selective to form (-)-mirror. Therefore, the present invention relates to a selective and dual method, using a selective oxidation and recycling method M to prepare a specific mirror phase or diastereomer of a CU-4 alkylsulfinylmethane sulfonium compound. Thing. This method can produce specific mirror or diastereomers, which can be used as D1 / D2 dopamine receptor antagonists, such as the better (-)-1- (9, 10-dihydro- 9,10-methanefluorene-9-ylmethyl) -4- (2-ethylsulfinamilide-3-pyrazinyl) hexahydropyridine-4-ol compound. This compound has an excellent increase in the D1 / D2 ratio, which indicates that it is extremely aggressive for treating patients with mental disorders. Its D1 receptor antagonist activity is similar to that of the D2 receptor antagonist, which balances D1 / D2 * and therefore has better clinical utility than traditional antipsychotics. Surprisingly -21- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) n —l-I-L I VI-Order

............. I g · 1ι · 1. = Ι I p 403744 V. Description of the invention (19), (-)-Mirror phase object has better D1 / D2 balance rate. Suitable pharmaceutically acceptable salts include organic addition salts with acids which form physiologically acceptable anions, for example, tosylate, mesylate, acetate, tartrate, citrate, Succinate * benzoate, ascorbate, fumarate, malate, alpha-glutarate, and alpha-glyceryl phosphate. Suitable inorganic salts are, for example, sulfate, nitrate, phosphate and hydrochloride. Known standard methods can be used. Pharmacologically acceptable salts are not obtained. For example, a suitable acid and a compound of formula I are inferior, and a pharmaceutically acceptable salt is obtained. Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). When used to treat mental illness or other neurological disorders, the compound of formula I or the compound that is preferably used is (- ) -1- (9,10) -dihydro-9,10-methane anthracene-9-ylmethyl) -4-(2-ethylsulfinyl-3-pyridyl) > hexahydropyridine-4 -Alcohol. This compound can be mixed with a pharmaceutically acceptable carrier or diluent and administered to a patient in need of an effective amount. The selected compound varies depending on the route of administration. This suitable pharmaceutical composition is Part of the invention. This sister compound can be obtained by traditional methods, such as traditional medicine attachments, excipients, fillers, inert ingredients, dispersants and the like. According to the preferred route of application, The active compounds and / or pharmaceutical compounds described above can be prepared in various dosage forms. Oral and axillary agents can include lozenges, micelles, solutions or suspensions. Intravenous, intracellular, subcutaneous, or intramuscular injection Or the perfusion dosage form is a sterile solution or suspension. For anal administration * Preparation of suppository compositions. The best route of application of the soluble salts in the present invention is the axillary armpit. More advantageously * in the present invention * the less soluble free amine or non-salt state * which can be used for sustained release or DEPOT formulation For patients-22- This paper size applies the Chinese National Standards (CNS) A4 specification (210X297 mm) Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 403744_ b7_ Five' Invention Description (20), the active ingredients of which can be used in Slow release to the patient over a suitable period of time. The present invention is limited to oral or DEPOT delivery methods. The method of using a therapeutically effective amount of the active compound of the present invention. Sustained release has generally been described in Remingtons Pharmaceutical Sciences Formulation and drug delivery method. In the treatment of mental patients, a long-term activating dose is required to continuously release and maintain the effective concentration of 5HT2 5-tryptamine, D1 and D2 dopamine antagonists in plasma. DEPOT prescription contains The above active ingredients can be implanted (for example, subcutaneously, through the skin, or intramuscularly) or injected intramuscularly. Here, 槩The above excipients, such as suitable polymers or hydrophobic substances (eg, emulsions in oil) or soluble salts, are formulated. The dose prescribed by DEPOT is selected so that the effective amount of the D1 / D2 / 5HT2 antagonist can be maintained The dose of a compound of formula I administered to a patient for a period of time will vary depending on the patient, its severity, weight, and specific biochemistry. Experienced practitioners can use the described range and patient The appropriate dosage will be determined by the conditions. Generally speaking, the compound of formula I will be used in patients (such as humans) to be treated so that it can receive an effective dose, and the dosage range is usually about 0.01 to about 10 mg / kg body weight. If used intramuscularly, the dosage range is from about 0.01 to about 5 mg / U body weight. However, for K orally, the range is about 0.1 to about 10 mg / kg body weight. It is known that compounds of formula I can be taken with other suitable therapeutic or prophylactic agents or drugs. The compounds of formula I are antagonists of the D1 and D2 dopamine receptors and are therefore useful as antipsychotics. In addition, the compound of formula I can be used as 5HT2 5-hydroxy color-23- This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page). -Order-Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 403744 V. Description of the invention (21) Amine receptor antagonists, therefore, can be used as antipsychotic drugs. These compounds have serotonin antagonist activity and a balanced D1 / D2 distribution. The antagonism of D1 and D2 and 5 Η T2 can be shown by the following standard tests. D2 antagonism can be performed using standard tests such as [3H] -Spi per one combined antagonism and / or morphine-guided climbing and morphine-guided interference with swimming. Other tests are as follows. The following is an open-ended example of the antagonistic effects of the compounds of the present invention on Dl, D2 and 5HT2 receptors, which show enhanced and balanced distribution of receptor antagonistic effects.

Test Round A is based on Sa 1 1 er and Sa 1 ama (J Pharm EXp Ther 2 ... 3-6 pg. 714, 1986) and Sailer et al. (J Pharm Exp Ther 25 3 pg. 1 162, 1990) After a small modification, M was used to quantify the receptor binding test for quantifying the affinity of compounds for dopamine D-1, dopamine D-2, and serotonin 5HT2 receptors. Briefly, the dopamine D-1 binding test was performed at 37 t: 15 points, in which 1.0 mM of 50 mM Tris-HCl * contained 120 mM NaCl, 5 mM KC1, 2 mM CaC12, and 1 mM MgC12 (out = 7.4 ), And a membrane of 3mgS and 3 mM [3H] SCH 23390 taken from the rat striatum. The dopamine D-2 binding test was performed in 37t: 15 points, which contained 1.01111 of 501 ^ 1 > 3-11 (: 1 (out = 7.7) including 40 nM ketanserin, taken from the rat pattern 4 mgs tissue membrane and 0.1 nM [3H] -Spiperone. The 5-hydroxytryptamine binding test was performed at 37 ° C for 15 minutes, which contained 1.0 ml of 50 niM Tris-HCl (cH = 7.7). Cortical membrane of 5 mgs and 0.5nM [3H] Ketanserin. Quick filtration using Whatman GF / B paper to stop all reactions. Use flicker-24- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 (Mm) (Please read the precautions on the back before filling out this page) Binding and ordering 403744 g Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (22) The counter determines the radioactivity on the filter paper. For Dl, D- The non-specific binding of 2 and 5HT2 is determined by measuring its binding activity in 1 // M SCH 23390, butaclamol or ketanser in, respectively, and subtracting K from the total binding to determine its specific binding. Each measurement Repeat at least three times. The determination of IC50 value is based on logit-log conversion of data. Regression squared. The value of Ki is determined according to this equation: Ki = IC50 / (L + Kd) * L = boundness of the binder in the test, and Kd = dissociation equilibrium of the radioactive binder measured in the saturation test Constants, such as * racemic di (9, 10-dihydro-9,10-methane anthracene-9-ylmethyl) -4- (2-ethylsulfinyl-3-pyridyl) hexahydropyridine The Ki values of pyridin-4-ol for Dl, D2, and 5HT2 receptors were 118 nM, 10 nM, and 21 nM, respectively. The Ki values of the pure (about 100%) L-isomers of the above compounds were 13 nM, 42 nM. And 39 test 酴 R After fasting about 20 g of female Swiss-Webster mice for about 24 hours, they were given multiple oral doses of vehicle or test agent (H = 20 mice per group). After 30 minutes, HCI morphine was given. , 1.25 ng / kg, sc, and placed in a climbing cage. The climbing cage is 9 cm wide, 15 cm deep, and 30 cn high. There are 27 horizontal steps on one wall with an interval of 1 cm. For the next 13 points, observe 1 point for each mouse, and record the highest and lowest rungs reached by its front paws. The average value of this score will be used as the record for the mouse (the highest and lowest scores are 27 and 0 respectively ). Climbing at 10 minutes After each of the mice was placed immediately circular swimming tank 2 minutes, and calculated the number of a spare tire. The height of the trough is 15 cm and its diameter is 28 cm. A circular obstacle with a diameter of 10.5 cm and a height of 17 cm is placed in the center of the trough to form a circular swimming trough, with a width of -25- This paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) —————— -r ---- 装-(Please read the notes on the back before filling this page) Order HI..L .-. il:!-'' 15 -'-'- '*. ο line 403744 5 Explanation of the invention (23) is 8.75 cm. The water height is 5.5 cm and the water temperature is maintained at room temperature. It is marked next to the floor and the tank, separated by 180 °. When the mouse swims from the marked side to the other side, it is recorded once. Use The mice were observed with a projection microscope, and the number of swimmings of 1 mouse at 80 ° was recorded. With a fixed dose of the test compound, the decline in climbing records was accompanied by an increase in the swimming score. The activity of this measurement was shown. The results of climbing and swimming will be expressed as ED50, ie when this dose can lead to a 50% reduction in climbing and a 50% increase in swimming. For climbing and swimming, typical ED50 results are 0.54 and 1.7 mg / kg po, respectively. In the above racemate, but for pure L-isomers is 1.3 and 1.6 mg / kg P.. S'-s--, _ -I---I 1 --- · nn--J-· (Please read the precautions on the back before filling out this page) Printed by Perese et al. (Brain .Research, 494. pg 285, 1989) mg of 6-hydroxydopamine was dissolved in 2wl of physiological saline, which contained 0.1 mg / ml ascorbic acid, and at least one month before the test, anesthetized male Sprague Dawley mice with pentyl E, and then injected the above solution into To its left black value. The divergent values obtained from the front window are: AP -5.2, L +2.0, V-7.5. Plexiglas cylinder rotometers (Columbus Insturments; Rota-Count-8) are used to detect its sequence. The clock and counterclockwise rotation behavior, and the number of rotations is recorded every 5 minutes throughout the duration of drug action. When animals are injected with L-D 0 PA (50 mg / kgi. P; t = 0) and benzerazide (3 0 mg / kg!. Mouth; 1; = -15 1 ^ 11) 2.5 hours after performance > 500 side turns, further analysis is needed. The counterclockwise rotation behavior is dopamine Dl selective activator, SKF 38393 induced dose-dependent behavior. Use the above -26- to order separately! ，. 0 line-This paper size is applicable to Chinese National Standard (CNS) A4 (210X297mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 403744 A7 _________B7 _ 5. Description of the invention (2 buckets) Racemic substances and 95 % Pure isomers to determine the paratolerant dose (20 mg / kg i.P.) of an antagonist of circling behavior induced by SKF 38393. At the same time (t = 0) SKF 38393 and racemate or 95% pure isomer were given, and the rotation behavior was recorded for 60 minutes. We found that the racemate has an IC50 value of 3.95 mg / kg Π.ρ.), (IC50 represents the drug concentration that can inhibit 50% of the rotation caused by SKF 38393), and the above-mentioned heteroaromatic hydroxy Ci-4 alkane Sulfinyl sulfinyl alkylsulfinyl sulfonyl l-isomer) with an IC50 value of 1.9 8 hi g / kg (i.p.).

In test D, male Sprague Dawley rats weighing about 60-120 g were fasted for about 24 hours, and M was orally administered with different doses of a vehicle or a test drug (N = 9 rats in each group). After 20. minutes, quipazine dimaleate, 2.5 mg / kg i.P. was administered and placed in a Plexiglass chamber alone. After 5 minutes, the number of head rotations is counted every 15 minutes. The average value was used to analyze the results, and the percentage of carrier and drug inhibition was calculated as ED50s, i.e. a dose that reduced the head rotation by 50%. The basic result is that the ED50s of the racemate is 0.61 mg / kg po and the ED50 of pure isomers (100%) is 1.38 mg / kg po. The present invention will be described by the following unrestricted synthetic examples, except as specifically proposed, which are: (i) temperature M photographic representation (C); operation and / or reaction at room temperature or normal temperature, that is, 18- 25Ϊ: range. (ii) using a rotary evaporator * under reduced pressure (600-4000 pascals; 4. 5-30 mmHg), and the temperature of the hot bath is 60¾ to evaporate the solvent; (Hi) fast color calendar chromatography Mmerck Kieselge'l ( Art 9385) or -27- The X degree of this paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) IL --- 一 ----- ^-(Please read the precautions on the back before filling this page )! Order 5 Μ, 1 U · 1 · 5 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (25)

Baker Flash Silican Gel; TLC B! J was performed on Analtech 0.25 mm silica gel GHLF plates (Art 21521), available from Analtech, Newark, DE, USA; (iv) Analysis by M High-pressure liquid chromatography (HPLC) analysis of the purity of the optically active mirror phase was performed on a 25cm X 4.6mm Chiralcel 0D. Or 15cm x 4.6mm Ultron Ovonucoid column, purchased from JT Baker, Inc .; and analyzed by M Most reactions and their end products were analyzed by HP LC using 25cm X 4.6mm Supelcosil LC-8-DB, or 25cm X. 4.6mm Supelcosil LC-18-DB columns, which were purchased from Supelco, State College, PA, USA Or 25cm x 4.6mm Zorbax RX columns. (v)-In general, MTLC or / and HPLC analysis is performed after the reaction, and the reaction time is only indicated by M; (νί) the melting point has not been changed, and (dec) represents cracking; the melting point is obtained from the above preparation; In some preparations, separation of substances with different melting points can lead to variability; (vii) Basically, all final products are purified by MTLC denier / or HPLC, and have good nuclear magnetic resonance spectroscopy (NMR) and microanalysis data (Vffi) yield is only described by M; (k) decompression unit is absolute pressure, pascals (Pa); and other pressures are measured pressures, bars; (X) chemical symbol, its meaning is as usual; meanwhile use the following symbols ·· v (volume) * w (weight), irp (melting point), L (liters), uL (ml), g (grams), mmol (millimoles) * mg (mg), nin (minutes), h (Hours); And this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) Binding and ordering A7 Β7 403744 V. Description of the invention (26) (xi ) Solvent ratio M is calculated by volume; (v / v > volume symbol. Example

Example 1-Method A (-)-Bu (9,10-dihydro-9,10-methanefluorene-9-ylmethyl) -4- (2-ethylsulfinamilide-3-pyridyl) hexa Hydropyridin-4-ol (titanium / tartrate / MOH) will be dissolved in dry methylbenzyl (425 bL) in nitrogen (-201 :) (-)-diethyl D-tartaric acid solution (18.55 g. 90.5 mmol), titanium tetraisopropoxide (14.47 mL, 45.25 mmol) was added dropwise. After stirring for 5 minutes, part of the solid 1- (9,10-dihydro-9,10-methanefluorene-9-ylmethyl) -4- (2-ethylsulfan-3-pyridyl) hexahydropyridine was added. 4-alcohol (20.0 g, 45.25 mmol). After maintaining this solution in -20 υ for 25 minutes, cool it to -78t! (Dry ice / acetone), and then add freshly dried t-butyl hydroperoxide (90%, 5.28 mL, 47.5 mmol) via syringe. ). Heat this flask to -15t: * 3 hours * after daring to sow * place the reaction in a -15¾ refrigerator for 18 hours. Add sodium hydroxide aqueous solution (1.0 N, 400 mL) to slow down the reaction. The suspension was diluted with K dichloromethane (50 in L) * and then the resulting mixture was filtered through diatomaceous earth and washed with DCM. The organic layer was separated. M dichloromethane (2 X 200 mL) was used to extract the water calendar. The organic extraction layers were mixed and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated under reduced pressure. The product was adsorbed on silica gel, and then purified by flash chromatography (10000 mL 'eluent: 20% formic acid / ethyl acetate to 30% > to obtain 17.63 g (the main compound of 85 is yellow / White solid. TLC analysis (Asian mill: Rf 0.24, smash / sulfide 0.73, Eluent: 15% formazan / acetic acid -29- The paper Λ degree applies to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page.) 111.1. ::-ll'-BrEB ± u .. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed 403744_ B7 _ V. Description of the invention (27) Ester > The mirror phase purity of this compound is 1: 3.7 ((+): (-)), and its HPLC analysis (Ultron ES-0VM 6.0 X 15 cn, mobile phase: 80% 0.01 M pH 7.0 phosphate buffer solution / 20% cyanomethane * flow rate: 1.0 fflL / min, up to 10 tfL injection, 2.0 retention time: isomer 1 * 13.4 min, isomer 2, 15.7 nin). The solid material was dissolved in hot toluene, cooled to room temperature, and then crystallized from the racemic sulfin. At 72 hours, this racemate slowly crystallized. Used Removal of solids. 11.73 g of Armenian oil was obtained with a purity of 5:95 (isomeric (+) / (-) ratio determined by HPLC). This oil was redissolved in hot methylbenzene * And allowed to recrystallize for 24 hours. At room temperature * the oily substance (7.7 g) was dissolved in methylbenzyl. After filtration, the M pure (-) isomer crystallized into seed crystals. After 4 hours at room temperature The crystal flask was placed in a -15TC refrigerator overnight. The obtained solid mud M cold toluene (Ot :, 15 nL) was diluted and then filtered. The white solid was dried under high vacuum and the residual solvent was removed. This step yields pure isomers (-) (6.9 g, analyzed by HPLC under high purity, yield is 33%, up 185-186ΊΟ (racemate: 206-208¾), optical rotation coefficient [a] -106 ° (c = 1.0, MeOH) / g / mL / dB ((+)-isomer, average optical rotation coefficient +117, c = 1.0, MeOH). Dissolve the free base in dichloromethane and K etherify HC1 was acidified * and K ether was diluted. The resulting hydrogen chloride salt was washed too much, washed with fresh ether, and then dried under vacuum (55¾, 10 pascal, 18 h) to obtain a white solid, BP subfluorinated 212-316XMdec). Hydrogen salt: 1H HMR (d6-DMS0, 300 MHz) 10.19 ( br s, 1H), 8.69 (d, J = 4.4 Hz, 1H), 7.63 (br d, J = 7.9 Hz, 1H), 7.57 (ι, 1H), 7.37 (m, -30- This paper is for China National Standard (CNS) A4 specification (210X297 mm) ---_-------- /-install-~ _ (Please read the notes on the back before filling this page) Order the Central Bureau of Standards of the Ministry of Economic Affairs Printed by employee consumer cooperative 403 * 744 a7 _B7___ V. Description of invention (2δ) 4H), 7.00 (m, 4H), 4.44 (b, 3H), 3.58 (η, 4H), 3.11 (m, 1H), 2.86 ( m, 1H), 2.76 (br s, 2H), 2.30 (br m, 2H), 1.97 (br m, 2H), 1.18 (t, J = 7.5 Hz, 3H), MS (Cl, CH4) m / z 459 (H + l, 100), 487 (M + 29, 16), 441 (21), 413 (12) Analysis: C28H3〇H2〇2S.1.8 HC1 Theoretical value: C, 64.15; H, 6.11; 5.34 Actual Values: C, 64.27; H, 6.46; H, 5.23 l £ UL :: __ Method B (oxaziridine oxidation reaction). Under nitrogen * will be dissolved in dry chloroform (or methylbenzyl) (8 ibL > 9, 10-dihydro-9, 10-methane anthracene-9-ylmethylhua) -4- (2-ethylthio-3-pyridyl) hexahydropyridin-4-ol (200 mg, 0.452 mmo 1) To the cold solution (-78¾) was added (S)-(+)-camphorsulfonyloxaziridine (104 mg, 0.452 mmol). The ice bath was removed and the reaction was allowed to return to room temperature. TLC analysis was used to detect its transition (TLC analysis: Rf 0.24, R / S 0.73, extract: 15% methanol / ethyl acetate). After a few hours, the starting material was still visible and no more oxidants were added to prevent oxidation. Add sodium hydroxide aqueous solution (1.0 N, 10 mL) to reduce the reaction. M dichloromethane (2 X 15 inL) was used to extract the aqueous layer. The obtained hydrazone extract was washed with M water, dried with anhydrous sodium sulfate, filtered, and dried under reduced pressure. The silica gel was subjected to flash chromatography to purify the product (50 nl, eluent: 10% methanol / ethyl acetate) to obtain 93 mg (45%) of the main compound as a yellow / white solid. The chromatographic purity of the compound obtained by HPLC analysis was 1: 5,6 ((+); (-)). The above steps can be improved (_ > _Isomers. -31- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page) • Installation-

2. Miu A7 B7 printed by the Consumer Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs. T. Description of the invention (29) The preparation method of the starting hexahydropyridin-4-ol is as follows: a. 9, 10 "dihydro-9, 10 -Methane-9-anthracenecarboxylic acid will be dissolved in acetone (260 mL) of cooled (0¾) 9-methylfluorenyl-9,10-dihydro-9,10-methylsulfonium (document preparation: wood. $ 111! 8 down 3% 8,6131

Chem. Pharro, Bull. Vο 1. 27 (1979) ρρ 1806-1812; U.S. Patent 4,2.2 4,344 Sunagawa et al., Sumitomo, Ltd .; September 23, 1980; U.S. Patent 4,358,620 $ 1111883 »3 61 a 1 · · Su ml tomo, L td.; November 9, 19 8 2) (7 8.5 mmo 1) Add a portion of the Jones reagent (24 nL; 27 g chromium trioxide, and dilute 23 mL of water to 100 nL of reagent solution). Add reagent to orange. The reaction containing exogenous chromium salt was warmed to room temperature. The vacuum method was used to remove the solvent, and the water was replaced (300 mL), and the sodium hydroxide was saturated. The aqueous phase was extracted with ethyl acetate (3 μmol). The resulting organic extract was extracted with 2.5 »1 NaOH (3 x 400 inL). M3 H HC1 acidified alkaline extraction aqueous solution, saturated with M sodium chloride, and then extracted with ethyl acetate (4 X 300 bL). The obtained organic extract M was dried over anhydrous magnesium sulfate, and after filtering, it was decompressed to obtain a white solid. This main compound. The yield was 80% white solid. MS (Cl * CH4) m / z 237 (M + 1, 100), 265 (m + 29, 10), 219 (22), 209 (15), 193 (20). b. 1- (9,10-dihydro-9, 10-methane anthracene-9-ylcarbonyl) hexahydropyridin-4-ol will be dissolved in toluene (70 mL) of 9,10-dihydro-9, To a solution of 10-methane-9-anthracenecarboxylic acid (24.1 mmol) was added thionyl dichloride (2.28 mL, 31.3 mmol, 1.3 eq). This reaction is heated to reflux, and M mineral oil is taken out -32- This paper is Α degree applicable to Chinese National Standard (CNS) Α4 size (210 X 297 mm) (Please read the precautions on the back before filling this page) • As installed · Order-=. Frub.ptiBE > Ei ~ ·-Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 403744 at B7 V. Description of the invention (50) The bubbler detects its gas generation. Within 40 minutes, the barnyard will reach a steady state, and it is said to be cooled, and 4-hydroxyhexahydropyridine (6.08 g, 60.3 mnol, 2.5e < i) is added. The reaction was exothermic and black. The reaction was heated at reflux for 2 h, cooled to room temperature and stirred for 18 h. Diluted with ethyl acetate (200 mL), and washed with M 3 N HC1 (2 × 100 mL >, 2.5 N NaOH (2 × 100 mL) and saturated brine (200 bL). This organic phase was dried over anhydrous magnesium sulfate. Filtered and reduced pressure to obtain an oil. The main compound obtained in this step was a quantifiable viscous oil. TLC analysis (Rf 0.54, 10% methanol in CHCU). MS (Cl, CH4) m / z 320 (M + 1, 100), 348 (H + 29, 22), 302 (16). C. 1- (9,10-dihydro-9,10-methane anthracene-9-ylmethyl) hexahydropyridine-4- Alcohol in nitrogen * will be dissolved in diethyl ether (200 mL), cooled (0¾), (9,10-dihydro-9,10-methane 葸 -9-ylcarbonyl) hexahydropyridin-4-ol (such as Lithium aluminum hydride (1.49 g, 39.2 mmol, 8 eq hydride) was added to the suspension (19.6 mmol). This suspension was soaked in ot! For 30 minutes, and heated to room temperature. At room temperature After 18 h in the middle * Add various solvents to remove excess reagents in the following order: water (1.5 inL), 2.5 N NaOH (1.5 mL) and additional water (4.5 mL). Stir this suspension until the aluminum salt appears White granular solid. Methyl acetate (100 mL) was used to dilute the suspension and a small amount of anhydrous sulfur The magnesium was dried and then dried. The filter cake M was completely washed with ethyl acetate. The solvent was removed to obtain a white solid main compound with 88% yield by TLC analysis (Rf 0.54, 10% methanol in CHCls) MS (Cl, CH4> m / z 306 (M + l, 100), 334 (M + 29, 14), 288 (62), 114 (8) ° -33- This paper size applies to China National Standard (CNS) A4 (210X297 mm) ( Please read the precautions on the back before filling this page). Packing. Order mmu A7 _ _B7 V. Description of the invention (31) d · 1_ (9,10-dihydro-9,10-methane anthracene-9-ylmethyl ) -4-piperidone under nitrogen, dissolved in 2.0 mL of dichloromethane (3.06 mL, 35.1 mmol, 2 eq) in dichloromethane and added to the condensed dimethylene Rhenium (5.00 mL, 70.2 mmol, 4 eq). After 10 minutes, 1- (9,10-diargon-9,10-methane anthracene-9-ylmethyl) hexahydropyridin-4-ol (as described in _h) (1.75 mmol) was dissolved in K dichloromethane. After the solution was added (10 * L) ° Before adding tristilum (19.6 nL, 140 bboI, 8 eq), the reaction was allowed to stir at -78 t: medium sowing for 30 minutes. Remove the cold bath and allow the reaction to warm to room temperature for 1.5 h. The reaction mixture was added to 2.5 H HaOH (100 mL), and the aqueous phase was extracted with M dichloromethane (3 × 100 mL). The obtained organic extract was dried over anhydrous magnesium sulfate, and when subjected to tritium, an oil was obtained under reduced pressure. K silica gel, and the crude reaction mixture (400 mL * eluent: 20% ethyl acetate in hexane) was purified by flash color chromatography to obtain the main compound as a white solid in 80% yield. TLC analysis (Rr 0.31, 2% methanol in dichloromethane). MS (Cl, CH4) m / z 304 (H + 1, 100), 332 (H + 29, 21) 〇e. 1- (9,10-dihydro-9,10-methane-9-methylformamide ) -4- (2-fluoro-3-pyridyl) -hexahydropyridine-4-enzyme printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Under nitrogen, To a cooled solution (-72¾) of distilled diisopropylamine (7.86 mL, 56.1 mmol, 1.3 eq) in THF / hexane (57 mL / 37 nL) was added η-butyllithium (2.5 M, dissolved in Hexane, 23.8 mL, 59.4 mmol »1.4 eq). The resulting solution was heated to -201 μM to ensure dehydrogenation, and then cooled to -72 t :. A solution of 2-fluoropyridine (4.50 nL, 5 3.5 mmol, 1.25 eq) (13 mL) in THF was added dropwise to obtain a yellow precipitate. The Chinese paper standard (CNS.) A4 size (210X297 mm) is applied to this paper size. 403744 A7 __________B7 V. Description of the invention (32) The gas reaction is heated to -50 ° C, 45 minutes, and it is cooled down to _72t! Immediately reached _30t :. Add human 1- (9,10-dihydro-9,10-methanefluorene-9-ylmethyl) -4-nezanet (as in the above id > (13.〇g, 429 『〇1) and solvent Lithium bromide (7.45 g, 85.8 mm, 2 eq) in THF (48 ml). During the addition, the yellow precipitate was dissolved and the reaction was heated to -20t :, 5 h, and acetic acid (10 mL) Slow down the reaction. After diluting the solution with M water (400 nU, then W2.5 N NaOH alkalization, M ethyl acetate extraction (3x300 bL). The obtained organic extract M was dried with anhydrous sodium sulfate, filtered and the pressure was eliminated to obtain a solid. The product was purified by recrystallization from ethyl acetate (3 crops), yielding 13.3 g (77%) of a white solid main compound. TLC analysis (Rf 0.22, 30% ethyl acetate in hexane). 1H HMR (CDCU, 300 nHz > (Please read the precautions on the back before filling this page). 8,09 (d, J = 8.2 Hz, 1H), 7.91 (dd, J = 8 .2, 9.4 Hz, 1H), 7.21 ( m, 5H), 6.94 (m, 4H), 4. 27 (s, 1H) 9 3.48 (s, 2H), 2.91 (m, 2H), 2.74 (m > 2 H), 2.62 (s, 2H) , 2.26 (m, 2H), 1.78 (b, 2H) 9 MS (C l, CH4) Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs * / ζ 401 (M + 1, 100), 429 (M + 29, 15K 383 (21). This free base is dissolved in acetic acid and acidified by HC1. This hydrogen chloride salt is washed with 濉 * Μ fresh ether and dried in vacuum (room temperature, 10 pascal. 18 h ) To obtain a white solid, mp 188-191T: (decomposition). Analyze C2eHaBFN2 0 · HC 1 · 0.4H2 0: Theoretical value: C, 70.31; Η, 6.08; N, 6.31 Actual value: C, 70.65; Η, 6.12 ; Ν, 5.83 f. 1- (9,10-dihydro-9,10-methanefluoren-4-ylmethyl) -4- (2-ethylsulfanyl-35- ^ Paper standard applies to China's national standard rate (CNS) A4 specification (210X297 mm) 403744 A7 B7 V. Description of the invention (33) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (3-pyridyl) hexahydropyridine-4-ferment under nitrogen, which will dissolve in Ι- (9, .ι〇-dihydro-9, 10-methanefluorene-9-ylmethyl) -4- (2-fluoro-3-pyridyl) hexahydropyridine-4 in THP (50 mL) -Leaven (e as above) (2.00 g, 5.00 mmol, 1 eq) was added with sodium thiosulfate sodium salt (0.90 g, 10.7 mmol * 2 · 2 eq). Under standard conditions, thiols were prepared using ethanethiol and sodium hydride. The reaction was heated to reflux for 18 h, and the reaction was stopped by adding water to reduce the amount of water (100 bL). M diethyl ether (2 × 100 mL) was used to extract the aqueous solution, dried over anhydrous sodium sulfate, filtered, and an oil was obtained under reduced pressure. The product was purified on a sand gel using a rapid chromatography method (200 mL * eluent: 50% ether in hexane). 2.00 g (90%) of the main compound was obtained. TLC analysis (Rf 0.29, 50% ether in hexanes> 1HNMR (CDCls, 250 MHz) 8.35 (dd, J = 1.6, 4.7 Hz, 1H), 7.58 (dd, J = 1.7, 7.7 Hz, 1H) , 7.22 (m, 4H), 6.95 (m, 5H), 4.27 (s, 1H), 3.58 (s, 1H), 3.48 (s, 2H), 3.28 (q, J = 7.3 Hz, 2H), 2.89 ( m, 2H), 2.80 (ddd, J = 9.3, 14.9, 10.7 Hz, 2H), 2.62 (d, J = 1.5 Hz, 2H), 2,12 (m, 4H), 1.35 (t, J = 7.2 Hz , 3H) MS (Cl, CH4) b / z 443 (M + 1, 100), 471 (H + 29, 16), 42 5 (25) This free base is dissolved in ether, and K etherified HC1 acidified The gasified hydrogen salt was filtered, washed with fresh M ether, and dried in vacuo (room temperature, 10 pascal, 18 h) to obtain a white solid, mp 176-179 (cracked). Analysis (: 28113 < ^ 205 * 211 (: 1 * 0.51120: Theoretical value: C, 64.11; H, 6.34; H, 5.34 -36- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back first (Fill in this page again) • Equipment.-· # Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 403744 V. Description of the invention (34) Actual value: C, 6 4.0 5; Η, 6.3 2; N, 5.2 6

mMJL 1- (9,10-dihydro-9 · 1__methaneanthracene-9-ylmethyl) -4- (2-ethylthio-3-pyridyl) hexahydromine: pyridin-4-ol @ Shed 1 Φ sulphide J5_M for treacherous cattle. The original procedure was in nitrogen. Zinc powder (1.72 g, 26.2 mm) was placed in a dry 500 mL round bottom flask, which contains a nitrogen inlet, and an additional funnel * Teflon-coated magnetic stirrer and thermocouple were used to add distilled tetrahydrofuran (200 mL, sodium / benzofluorenone group) to the reactor using a cannula to cool the resulting suspension to 〇t: 0.44 mL of titanium tetrachloride, 13.1 mmol, just distilled) was added to the zinc suspension in the rapid stirring to make it relocate. When the reaction of zinc starts, the initially formed titanium tetrachloride-tetrahydrofuran complex (yellow > i.e. rapid decomposition. After stirring for 10 minutes, it is added dropwise in tetrahydrofuran (50 mL) as the substrate of the substrate (9,10 -Dihydro-9,10-methanefluorene-9-ylmethyl) -4- (2-ethylsulfinamilide-3-pyridyl) hexahydropyridine-4-enzyme (1.50 g, 3.27 mmol) to Gray / blue titanium (II) suspension. Immediate reaction produces titanium (II) suspension (purple / black). The cold bath was removed * and the reaction was maintained at room temperature for 2 hours. Water (100 mL) and aqueous sodium hydroxide solution (2.5 N, 100) were added to stop the reaction. M ethyl acetate was used to extract (2 X 250 bL) the aqueous phase. The obtained organic extract was dried over anhydrous sodium sulfate. After filtering, an oil was obtained under reduced pressure. TLC analysis (Rf 0.29, 50% ether was dissolved in hexane) gave the only product. Purification of the reaction product, dissolving it in hot methylbenzene (10, then M heat Diluted with hexane (20 inL). After heating under reflux, the solution was filtered and cooled to room temperature. When the sulfide crystallized, the recrystallized strips were cooled to -37- This paper size applies Chinese National Standard (CNS) A4 Specifications (210X297 mm) (Please read the precautions on the back before filling this page). Install. Order A7 B7 Repair 8 £] | 〇6463 Patent Application Form Correction Sheet (June 87) I "丨 丨丨 _ lf V. Description of the invention (VIII) 741 0 ° C. After a few hours, remove the solvent and dry the solid under high vacuum (room temperature, 10 Pascal, lh). This step yields 1.25 g (86 4 %) Yellow solid main compound 'which has analytical purity by NMR analysis. IH NMR (CDC13, 250 MHz) 8.35 (dd, J = 1.6, 4.7 Hz, 1H), 7.58 (dd, J = 1.7, 7: 7 Hz, 1H), 7.22 (m, 4H), 6.95 (hi 5H), 4.27 (s, 1H), 3.58 (s, 1H), 3.48 (s, 2H) , 3.28 (q, J-7.3 Hz, 2H), 2.89 (m, 2H), 2.80 (ddd, J = 9.3, 14.9, 10.7 Ηε, 2H), 2.62 (d, J = 1.5 Hz, 2H), 2.12 ( m, 4H), I.35 (t, J = 7.2 Hz, 3H) MS (Cl, CH4) m / z 443 (M + l, 100), 471 (M + 29, 16), 425 (25) following Exemplified is the preferred step for preparing the main compound. Section D Example 3 (-)-1- (9,10-dihydro-9,10-methaneanthracene-9-ylmethyl) -4- (2-ethylidene) Fujiki-3-¾ steepyl) hexahydrostigmine-4-ol in nitrogen 'will dissolve the diethyl D-tartrate (2.10 moles) in non-dried toluene and cool to dissolve and add tetraisopropyl titanium oxide ( 1.06 moles); 1- (9,10-dihydro-9,10-methane anthracene-9-ylmethyl) -4- (2-ethylsulfan-3-pyridyl) hexahydropyridine-4-ol ( 1.0 moU) and t-butyl hydroperoxide (1.18 moles). After the reaction was allowed to proceed for 48 hours, a 2N NaOH solution was added; the solid T i 0 2 was removed by filtration, and the solvent was evaporated to obtain a preferred main mirror phase with a ratio of 8: 1 (65-70% yield). Recrystallization in MeCN yielded (-) mirror phase in 72% yield; nip 185-186 with a specific optical rotation of [α] -106 (1.0 in MeOH). -3 8-This paper size applies to Chinese National Standards (CMS > A4 size (2l0X 297_mm) (Please read the notes on the back before filling this page) -I. Order by the Central Bureau of Standards of the Ministry of Economic Affairs. Printed by the employee consumer cooperative A7 B7 403744 V. Description of the invention (36) Preferably, the starting 2- (ethylthio-3-pyridinyl) -hexahydrolaridine-4-ol compound * is prepared as follows: a. 9-Methylfluorenyl-9,10-dihydro-9,10-methane anthracene. Tricyclic aldehyde shown in Table 1 (X and Y are fluorene) as 1 ^ * in a tube closed in 180 C Reacted with ethylene diene acetate (7.17 eq) (or purchased) to produce the ethane aldehyde shown as li in Scheme 1. At 20-25 t: in H2O / acetone (1.96 / 7.7 vol) The corresponding 9-carboxylic acid ethane anthracene was obtained by Jones oxidation (Cr03 / H2S04), and the table is 1_5_. In 90-95 t :, ϋ (χ and Υ = Η) and diphenylphosphonium azide (6.85eq) and triethylamine (NEt3, 1.2 eq) in methyl isobutyl hydrazone (MIBK), with the corresponding intermediates hydrazone nitrogen and isofluoride * in MIBK M100 Tw UaOH (10 eq ) After treatment, a 66% yield of primary amine (isolated from HC1 in MIBK) The table in the process is 2iL. Using NaN02 / H0Ac (1.5 eq / 25 eq> in H2O, M diazotization, the primary amine undergoes a ring contraction reaction. After neutralization and encountering K0Κ, 90% yield of Initial methanal. In addition, M acetic acid (0.5 vol); dissolved in methyl benzyl 1.18 mHCl (0.5 vol) and reacted with diphenylphosphonium sulfonium nitrogen * to treat the intermediate isocyanate to obtain the primary amine 2LiL ( X and Y = H), the yield is 72%, and the above-mentioned diazotization reagent is used to perform ring shrinkage using an anionic carbohydrate intermediate to obtain 90% yield of methanal. B. Bu (9,10-II) Hydrogen-9,10-methane anthracene-9-ylmethyl) -4-Bniridone. The methanaldehyde (1.0 mole) and hexahydropyridine-4-ethylacetal (1.5 mole) produced in step a. Above. Reaction; at 2510, reacted with 8H BH / py (0.45 mole) in MeOH for 4 hours, M produced protected acetal. The paper size is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) (please read the back first) (Notes on this page, please fill in this page again) Pack. ， Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer ’s Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed by 403744 37) (9,10-dihydro-9,10-methane-9-ylmethyl) -4-piperidine_, and then deprotected by the following sequential processing steps (1) ^ HC1 (reflux · 2 hours * 2X) and (2) at 85t: 'Treat with 47% HaOH solution to> 8 to precipitate the product (4-piperidone main compound) to 79% yield. c. Bu (9, 10-dihydro-9,10-methane anthracene-9-ylmethyl) -4- (2-fluoro-3-pyridyl) -hexahydropyridine-4-enzyme from nBuLi and isopropylamine LDA (1.1 moles) is generated and reacted at -70t! With 2-fluoropyridine U .1 moles) to form a pyridyl anion, which is then reacted with 4-piperidine hydrazone produced in step b to form the main compound . M AcOH stopped the reaction and was distributed in Η 20 / toluene and recrystallized from toluene with a yield of 66%. d. 1- (9,10-dihydro-9,10-methanefluorene-9-ylmethyl) -4- (2-ethylthio-3-pyridyl) -hexahydropyridin-4-ol pair step c. In the main compound solution (1.0 mole), add 2 moles of EtSH, 4N HaOH (2.5 moles) ′ dissolved in pivalolone and react in 901 for 7 hours. After allowing it to stand in H2O / toluene, methylbenzene was allowed to evaporate, and the main compound was crystallized from isopropanol with a yield of 79%. This compound is used to make (-)-1- (9,10-dihydro-9,10-methane anthracene-9-ylmethyl) -4- (2-ethylsulfinamilide-3-pyridyl) ) -Hexargyridine-4-ol crystals. The following paragraphs describe a typical dosage form of a drug, which contains a compound of formula I selected from pure or partially pure form, which is (-bubu (9,10-dihydro-9,10-methaneanthracene-9- Methyl) -4- (2-ethylsulfinyl-3-pyridyl) hexahydropyridin-4-ol. The suspected preparation containing the above-mentioned compound (50.0 mg) can be used as a cure-40 * · This paper Standards are applicable to China National Standard (CNS) A4 specifications (210X297 mm) (please read the precautions on the back before filling out this page) • Equipment-Words of the Ministry of Economic Affairs, China Standards Bureau, Consumer Consumption Du printed 403744 A7 B7 V. Invention Note (38) Treat or prevent human diseases and may contain pharmaceutically acceptable excipients such as mannitol, USP (2 23.75 mg); croscarmellose sodium (6.0 mg); corn starch (15.0 mg ); Hydroxypropyl methyl cellulose (2.25 ng) and magnesium stearate (3.0 mg). The micelles containing the above active ingredient (10 mg) for the mouth and eyes may contain pharmaceutically acceptable excipients, Such as mannan, USP (488.5 rag); sodium carboxymethylcellulose (15.0 mg >) and magnesium stearate (1.5 mg). Suitable oil preparations can be prepared using the following * For example, a mixture of the above compound free base and 25% glycerol in water. It can be used in, for example, micelles or other suitable delivery methods. The above formulations can be prepared by conventional methods or other known methods. The above examples are not for this invention Set limits, and other known or traditional pharmaceutically acceptable excipients or diluents can also be added to the active ingredient K to form a pharmaceutical composition, which can be used to treat abnormalities in spirit, including the spirit to be treated Abnormal patients. The present invention is based on a pharmaceutical composition, which comprises the effective amount of the active compound described above and a known pharmaceutically acceptable carrier mixture. The present invention is based on the dopamine receptors (D1 and D2). Of antagonism or 5-hydroxytryptamine 5HT2 stimulant, which is to antagonize the receptor separately, including the treatment of patients in need of treatment, to provide an effective amount of the compound or compound of the present invention as an antagonist The present invention relates to the treatment of neurological abnormalities caused by D1, D2 or 5HT2 receptors or activation of the event *, including the administration of a compound according to formula 1 in an effective antagonistic dose. -)-1- (9,10-dihydro-9,10-formamidine_9-yl-methyl) -4- (2-ethylsulfinyl-3-pyridyl) hexahydropyridine- 4- Fermentation has good equilibrium solubility in aqueous and non-aqueous solutions, and maintains its-41- in the solution. 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1T 403744 A7 B7 V. Description of the invention (39) Chemical and stereochemical stability. Its free amine compounds are also highly non-hygroscopic. (Please read the precautions on the back before filling out this page) Packing. S.FLUlEr-_ Ordered by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 42- This paper size applies to China National Standard (CNS) A4 (210 X 297) (Centi) 403744 V. Description of the invention (4〇A7 B7 chemical formula

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Process I

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Process II

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Claims (1)

Patent Application No. 83106463 Chinese Patent Application Amendment (June 89) Patent Application 403744 (Please read the notes on the back before filling this page) 1. A compound of formula I Among them, X and Y hydrogen; R1 is 2-U1-4C) alkylsulfinamilide] -3-pyridyl, and pharmaceutically acceptable salts thereof. -2. The compound according to item 1 of the scope of patent application, in which X and Y are Η, and R1 is 2-ethylsulfinamilide-3-pyridyl and a pharmaceutically acceptable salt thereof. 3. The compound according to item 1 of the scope of patent application, which is (-)-: 1- (9, 10-dihydro-9,10-methaneanthracene-9-ylmethyl) -4- (2-ethyl Sulfinyl-3 -pyridyl) hexahydropyridin-4-ol, characterized in that the compound is crystalline and its pharmaceutically acceptable salts. Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 4. The compound according to item 3 of the scope of patent application, characterized in that the melting point of the crystalline compound is 1 8 5-1 8 6 t, and its specific optical rotation is [α] -1 〇6. (c = 1.0, soluble in MeOH) and non-hygroscopic. 5. The compound according to item 1 of the scope of patent application, which is (-)-1- (9, 10-dihydro-9, 10-methanefluorene-9-yl (methyl) -4- (2-ethyl Sulfinyl) -3 -pyridyl) hexahydropyridin-4-ol, characterized in that the compound is crystal, which has good equilibrium solubility in water-soluble and water-insoluble media, and can maintain its solubility in solution Chemical or Stereochemical Stability This paper size applies to China National Standard (CNS) A4 (210X297 mm) Patent Application No. 83106463 Chinese Patent Application Amendment (June 89) Patent Application 403744 (Please read the notes on the back before filling this page) 1. A compound of formula I Among them, X and Y hydrogen; R1 is 2-U1-4C) alkylsulfinamilide] -3-pyridyl, and pharmaceutically acceptable salts thereof. -2. The compound according to item 1 of the scope of patent application, in which X and Y are Η, and R1 is 2-ethylsulfinamilide-3-pyridyl and a pharmaceutically acceptable salt thereof. 3. The compound according to item 1 of the scope of patent application, which is (-)-: 1- (9, 10-dihydro-9,10-methaneanthracene-9-ylmethyl) -4- (2-ethyl Sulfinyl-3 -pyridyl) hexahydropyridin-4-ol, characterized in that the compound is crystalline and its pharmaceutically acceptable salts. Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 4. The compound according to item 3 of the scope of patent application, characterized in that the melting point of the crystalline compound is 1 8 5-1 8 6 t, and its specific optical rotation is [α] -1 〇6. (c = 1.0, soluble in MeOH) and non-hygroscopic. 5. The compound according to item 1 of the scope of patent application, which is (-)-1- (9, 10-dihydro-9, 10-methanefluorene-9-yl (methyl) -4- (2-ethyl Sulfinyl) -3 -pyridyl) hexahydropyridin-4-ol, characterized in that the compound is crystal, which has good equilibrium solubility in water-soluble and water-insoluble media, and can maintain its solubility in solution Chemical or Stereochemical Stability This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm). Printed by A8 B8 C8 D8 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 6. Scope of patent application. 6. A pharmaceutical compound as a dopamine antagonist, which includes the compound according to item 1 or item 5 of the scope of patent application or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier and Thinner. A method for preparing a compound according to any one of items 1 to 5 of the scope of the patent application. Or a pharmaceutically acceptable salt thereof, which comprises oxidizing a compound of formula I, wherein X and Y are as described in the scope of the patent application. As defined in any one of items 1 to 5, and R1 is 2-[(l-4C) alkylthio] -3-pyridyl, using a palm symmetry oxidation step, the formula alkyl S Selective oxidation of the (1-4C) alkylthio group in the mirror phase to form palmitic symmetrization of the formula Cl_4 alkyl SO, resulting in a compound of formula I as defined in any one of claims 1-5 Wherein the spectroscopic selective oxidant is selected from the group consisting of titanium / tartaric acid / peroxide mixtures and palm symmetry; and when a pharmaceutically acceptable salt is required, the compound of formula I can react with an acid to produce a physiologically acceptable Accepted anions * or react with bases to provide physiologically acceptable cations. 0 A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 of the patent application scope, comprising: : (A) Corresponding to piperidone of formula II in a non-hydrogen solvent Reaction of a compound of formula PU: This paper size applies to Chinese National Standards (CNS) M specifications (210 X 297 mm) (please read the notes on the back before filling this page) 403744 ll D8 6. Scope of patent application (b) react the corresponding amidine of formula Ila with a suitable reducing agent; I Ha (c) reacting an aldehyde of formula III (G is hydrogen) with the corresponding hexahydropyridine of formula IV in the presence of a primogen; or (Please read the notes on the back before filling in this page) ΠΙ hCP1 w Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, and then the compounds obtained by (a), (b) or (c) will be selected with mirror The oxidant is selected from the group consisting of titanium / tartaric acid / peroxide mixture and palm symmetry 噚 K a (Ziridine); and when a pharmaceutically acceptable salt is required, the compound of formula I and the acid Reaction, which can generate physiologically acceptable anions, or react with alkali * This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm). A8_4〇3744 __i 6. Application for patent scope 9. Hydrogen dioxin and hetero ο yang, 1 of (9 accepts 1-connected)-can (-epithelial crystal growth and seed production to increase yield can be one of its alkyl methyl methyl method methyl square sulfonyl ethylene Hydroxyl / 1 / pyrimidinyl will include its hydrodialkylmethyl alcohol 4-yl I ® 9-% w 'thioethylpyridinyl hexalite wine-D's benzyl water. In contrast to the solvent dissolution, the same alcohol and other 4- or liquid-soluble but cold-based pyridyl esters of pyridinium 3 di-acid sulfonium or other sulfonyl or CN CN J e BM, such as rich in hydrogen-solubilizing oxygen The suitable base is composed of Ding Zai-its special, and the titanium compound and oxygen mixed propane heterophase four-mirror diagnosis needs to be made. The object can be constructed. The different, agent-phase object mirror-mirror)-chemical (-Therapy of pure items is ruled into the third class of life, and the profit of the surrounding people is often special and different. Please apply for sex-Shen Shenzhe according to the essence and cure (please read the precautions on the back before filling this page) Order Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 4 This paper is in accordance with the Chinese National Standard (CNS) Α4 specification (210X297 mm)