TW200804398A - Process for preparing bicyclic pyrazolyl and imidazolyl compounds - Google Patents

Abstract

A process for preparing compounds of Formula (I) are described herein where A, B, R0a, R0b, R1a, R1b, n, m, X, R3a, R3b, and R4 are as defined herein. The crystalline form of 3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-7-(2,2-difluoro-propyl)-6,7-dihydro-2H,5H-4-oxa-1,2,7-triaza-azulen-8-one which is prepared by this process is also described herein.

Description

200804398 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a method for preparing a bicyclic μ group and a (4) group compound, specifically, 3 (4-chloro-phenyl)-2-(2) -Chloro-phenyl)-7-(2,2-difluoro-propyl)-6,7-dihydro-2H,5H ice-oxatriazane-chamomile 'cycloxanone' and used to synthesize this An intermediate such as a bicyclic compound. The bicyclic (tetra) and (iv) based compounds prepared by the methods described herein have been shown to be CB-1 receptor antagonists. [Prior Art] It has also been known that CB-1 antagonists can be used to treat various diseases and diseases including obesity, alcoholism, smoking cessation, Parkinson's disease, inflammation, sexual dysfunction, dementia and the like. And / or disorders. Therefore, there is a need to develop compounds that selectively antagonize the CBq receptor. U.S. Patent No. 2005/0101592 and PCT Publication No. 5/〇44822, the disclosure of which is incorporated herein by reference in its entirety in its entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire all However, there is a need in the industry to produce such compounds in a more efficient, environmentally safe and cost effective manner and on a larger manufacturing scale, specifically 3-(4 _ vaqi)-2-(2-gas-phenyl) 7-(2,2-Difluoro-propyl)_6,7-dihydro-. 2H,5H-4-oxa~n?-triaza-chaemarinone. SUMMARY OF THE INVENTION The present invention provides an improved process for the preparation of a compound of formula (1), a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound or salt: 114897.doc 200804398

Wherein R〇a R〇b or A is carbon and B is nitrogen; (cc, r, RW and heart are each independently dentate, (C)-(5) alkoxy, (CVC4) alkyl, self-primed ^ Produce ', (C1 * C4) alkyl or cyano (preferably, reverse gas, rat or 曱 01) 卜 ^ gas, fluorine or hydrogen (ie, m is 0); Chaotic, gas, ((VC4) alkyl, trifluorobenzene, τ, (C-C4) succinyl or murine, and Rlb is hydrogen (ie, n is 〇)); η and m are independent Is 〇, i or 2; is S, S〇, S〇2, -N(R2a)- or a C(R2b)(R2c)... wherein one and R are each independently hydrogen, (Ci_C4) alkyl, Halogen substituted (1, C4) alkyl or (Ci_c5) fluorenyl; (preferably, R2a is hydrogen, (Ci_C4) leumino or fluoro substituted (Ci_C4) alkyl); and R2b & R2^ has at least a system ((VC4) alkyl or fluorine substituted (Ci_C4) alkyl, or both R2b and rZc are hydrogen); R and R are each independently hydrogen, (C^C6) alkyl or substituted by halogen And (C. Fully or partially saturated 5- to heterozygous 114897.doc 200804398 wherein the heterocyclic ring comprises - selected from the group consisting of oxygen, nitrogen or sulfur, and optionally substituted by one or more substituents; : The chemical part of the group consisting of: ((vc8) alkyl, aryl carbocyclic, diocta-based (5) alkyl, 3_ to 8-member partially or fully saturated and 3 5S (hetero, 5 to 6 members) Internally brewed, ...-infantamine • shell partially or fully saturated heterocyclic ring, wherein the chemical moiety is replaced by one or more substituents as appropriate, and two mR3a or R3b are formed to form a complete or partial saturation. The heterocyclic ring may optionally comprise a heteroatom of the selected material and may be substituted by one or more substituents as appropriate. The melon-carriage is preferably selected from the group consisting of Chemical moiety: (Ci_c) alkyl group, aryl core c4m group, 3_ to 8_ member partial or complete residue and carbocyclic 丄 3=8-shell partially or fully saturated heterocyclic ring, the chemical moiety may be Substituting one or more substituents, or R4 and RSa or forming a fully or partially saturated 5- to 61 heterocyclic ring, wherein the heterocyclic ring Ring-shaped ring = can be substituted by one or more substituents. More preferably, R4 is a CrCd alkyl group, which is substituted by a sulfonate (Cl-C8) group (preferably substituted by a sulphur (Ci•^ a group, a cyclopentyl group, a cyclohexyl group, a hexahydroindole, a quinone, a hydrazine, a quinone or a phenyl group. Preferably, R12, 2-difluoropropyl. A', preferably, A is nitrogen and B is carbon. R3a & R3b are preferably all hydrogen. The process for the preparation of a compound of formula (I) comprises the steps of: cyclizing a compound of formula (I-a) in the presence of U'-carbonyldiimidazole to produce a compound of formula (1) 114897.doc 200804398

Wherein R is hydrogen and A, B, R〇a, R〇b, Rla, RIb, n, m, X, R3a, R3b and R4 are all as defined above; and (2) isolating formula (1), and its medicine An acceptable salt, or a hydrate or solvate of the compound or the salt. Alternatively, it may be initiated wherein R is an alkyl ester. The ester group is hydrolyzed to the corresponding slow acid (i.e., the compound of formula (I-a) wherein R is hydrogen), followed by formation of the final product (i.e., the compound of formula (1) as described above). Preferably, the compound of formula (1) is isolated as the compound name, or a hydrate or solvate thereof. In a preferred embodiment, the compound of formula (I) is 3 gas clasp chlorophenyl-chloro-phenyl)-7-(2,2·dipropyl)_6,7·dihydro-2H,5H_4• Oxygen-u,? · Triaza-chamomile-8-one (ie, A is nitrogen 'b is carbon, both are ruthenium, R〇a and both are chlorine, Rh and both are hydrogen and "is 2,2_difluoro-positive Base) When A is nitrogen, B is carbon, both are 〇, R〇a and r1c are all chlorine, ^ and R3t^ are hydrogen, X is oxygen, and is one piece, -fluoro-n-propyl group, The compound (Ia) is preferably prepared by the following: (1) coupling a compound of the formula (1_2) with a compound of the formula (Hi) to give a compound of the formula (I-2c-1) 114897.doc 200804398

Cl (l-2c-1) wherein Pgi is a carboxy-protecting group (such as ethyl), and! >§2 is an amine-protecting group (for example, -C(0)0C(CH3)3 or B〇c); and (11) removing the amino-protecting group (pg2) and the carboxy-protecting group Group (Pgi) to produce the compound of formula (I-la). In another embodiment of the present invention, there is provided a 3-(4-gas-phenyl)_2_(2-chloro-phenyl)-7-(2,2-difluoro-propyl).6,7·2 prepared by the above method. Crystal form of hydrogen-2Η,5Η-4-oxa-1,2,7-triaza-chaemarinone. In another embodiment of the present invention, there is provided a 3-(4-va-phenyl)-2-(2-chloro-phenyl)-7-(2) having the X-ray diffraction pattern illustrated in FIG. A substantially pure crystalline form of 2-fluorodipropyl-2,7-dihydro-2H,5H-4-oxa-1,2,7-triaza-chamomile-8-one. The above method can provide advantages over the previously described methods. For example, the method of the present invention avoids the use of halogenated solvents, such as 1,2-diqi B, as compared to the previously disclosed routes (see U.S. Patent No. 2005/010 1592 or PCT Publication No. WO 05/044822). alkyl. In addition, the product can be separated directly from the reaction mixture via precipitation, thereby eliminating additional separation steps and reducing impurities. Definitions 114897.doc -10- 200804398 The term "shallow" as used herein refers to a hydrocarbyl group of the formula (f). The alkane group may be linear or branched. For example, the term "(c^cj alkyl, refers to a monovalent straight chain or branched aliphatic group containing from 1 to 6 carbon atoms (eg methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, second-butyl, tert-butyl, n-pentyl, methyl butyl, 2-methylbutyl, 3-methylbutyl, neopentyl a group, a 3,3-dimethylpropyl group, a hexyl group, a 2-methylpentyl group, and the like. Similarly, an alkoxy group, a fluorenyl group (for example, an alkyl group), an alkylamino group, a dialkylamino group. And the alkyl moiety of the alkylthio group, ie, the alkyl moiety, has the same definition as above. When indicated, as the case may be substituted, the alkane or alkyl moiety may be Substituted or optionally substituted one or more substituents (generally 1 to 3 substituents, halogen substituents such as perchloro or perfluoroalkyl), independently selected from the group of substituents listed below In the case of the following, the term "alkyl substituted by halogen" means an alkyl group substituted by one or more atoms of a s-platin, for example, an alkyl group substituted by fluorine, which means a gas methyl group, two Methyl, trifluoromethyl, 丨-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, trifluoroethyl , 2,2,2-trifluoroethyl, 1,1,2-trifluoroethyl, l52,2-trifluoroethyl, 1,2,2,2-tetrafluoroethyl, 1,1, 2,2-tetrafluoroethyl, mi tetrafluoroethyl, 1,1,2,2,2-pentafluoroethyl, 1,1,1,2,2-pentafluoroethyl, perfluoroethyl, etc. Preferably, the alkyl group substituted by the functional group is a gas and a fluorine-substituted alkyl group, more preferably a fluorine-substituted alkyl group. When substituted, the alkane group or the alkyl moiety is preferably substituted by fluorine. Substituted (as described above), or substituted with deuterium or two substituents independently selected from: ((VC0 alkyl, (CVC6) cycloalkyl, (c) alkenyl, aryl, heteroaryl 3- to 6-membered heterocyclic ring, chloro, cyano, hydroxy 114897.doc -11 - 200804398 yl (crC3) alkoxy, aryloxy, amine quinone c Γ, 卜# amine group, (c) -c6) alkylamino group, 14 alkylamino group, urethane (ie (c C) η ΝΗ-), hydroxyme p (Ci-C3) alkyl-〇-c(〇)- Fluorine group, or cation (milk), and more preferably 1 to 3 The next one is selected from the group consisting of the following substituents: C6) cycloalkyl, (c (1, (c3-), 3- to 6-membered heterocyclic, (c, 242, alkyl) Or two (kc2 alkylamino group. What is deducted. 卩 or fully saturated carbon ring " (also (10) means partially or fully hydrogenated and can be used as a single: two saturated 被#韭t 』1 is early &, double or spiral ring, square incense loop. Unless otherwise stated, 兮 _ $, g ^ aid. Α 系 石 石 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 通常 : : : : : : : : : : : _ base) package (tetra), cyclopentadienyl, cyclohexyl, cyclohexyl: yl 2 'cyclopentanyl (bicycloheptyl), norbornene / monoalkenyl, reduced as "heptyl" Descending alkenyl, bicyclo [2.2.2] octyl and bis and bis are indicated as, and may be replaced by " as appropriate, then partially saturated with U and may be unsubstituted or independent Substituted from the "婉 substituted" group of substituents listed in the definition, one or more of which are substituted for 1 to 3 substituents. (, hanging to eight to m ^, the slaves replaced by the work also include the carbon ring thick system: diammonium). The carbocyclic group can be attached to the chemical entity or moiety by the carbon. When substituted, the carbocyclic group is preferably taken from 1 or 2 substituents independently selected from the group consisting of = (Cl-C3) alkyl, 3) dilute, ortho, aryl Heterophyllum, heteronuclear, chloro, fluoro, cyano, hydroxy, (c)-c3) alkoxydithiolate, amine group, (CVC6) phenanthrenyl group, two common c4) phenanthrenyl group, 5 women a base acid vinegar (i.e., (p (cvc3) alkyl-7-C(0)-NH, hydroxy (Cr 114897.doc 12 200804398 CO alkylamino or keto (oxo), and more preferably, From 1 or 2 independently selected from ((VC)) alkyl, 3 to a heterocyclic, fluorine, (Ci_C3) alkoxy, (1) (5) alkyl or di-(C^c: 2) alkyl Substituent substitution of an amine group. Similarly, any cycloalkyl moiety of a group (e.g., cycloalkylalkyl, cycloalkylamino, etc.) has the same definition as above. The term "partially saturated or fully A saturated heterocyclic ring " (also known as "partially saturated f fully saturated heterocyclic ring") means a non-aromatic ring which is partially or fully hydrogenated and which may exist as a monocyclic, bis- or snail. Unless otherwise stated, The heterocyclic ring usually comprises independently selected from the group consisting of sulfur, oxygen and/or nitrogen. a 3 to 6-membered ring of up to 3 heteroatoms (preferably or a hetero atom). A partially saturated or fully saturated heterocyclic ring includes groups such as epoxy, aziridine, tetrahydrofuran , dihydro cough base, H-based, material π-base, N_methyl D ratio slightly bite base, ° 嗤 ° ° fixed base " rice (four)-based 'hexachloro-n-bite base, hexachloropyridazinyl> ratio Stationary, 2Η·° 喃 基, 4 Η·° 喃 、, 2 Η benzopyranyl, ♦ ♦ soil, morphine, thiophenanyl, tetrahydrothiophenyl, tetrachloro phenyl phenyl] 2: Compounds and the like. When indicated as "as appropriate, ", where: Knife saturated or fully saturated heterocyclic groups may be unsubstituted or may be substituted by the ones listed in the definition of "substitution". Substituting from the bottom to the three substitutions " one or more substituents (generally to three substituents) to replace ... substituted heterocyclic ring package "heteronucleotide ring fused to aryl Or a heteroaryl ring group: a homofuranyl group, a 2,3-dihydrof group, a 2,3_, a-fluorene benzene benzo (tetra), etc.), when substituted, a bis-open thiobenzene Base, 2, 3- 2: independently selected Substituted substituents: (c interesting group = yl, (cvc4) alkenyl, aryl, heteroaryl (3 core) per alkane to beryl ring, chlorine, I I4897.doc -13 - 200804398 : base = , mercapto, (C]_C3) alkoxy, aryloxy, amine, (... bis(Cl-C3) alkylamino, amino carboxylic acid vine (ie, (Cl-C3) alkyl- 0-C(0)_NH_) or (Ll Cs) Li, g ό Μ a soil (milk generation), and more preferably, 1 or 2 unique = selected from (C) Qianji, (W (C6) Aryl group, 6_member 蜀 two:: Γ: substituted by a heterocyclic ring or a gas substituent. The heterocyclic group may be attached to a chemical entity by any ring atom in the far-leaf-like soil system, any heterozygous portion of a group (such as a heterocyclic-substituted alkyl group, a heterocyclic group, etc.) All have the same definition as above. ""aryl" or ", aromatic carbocyclic ring" means an aromatic moiety having a -monocyclic system (eg, benzene) (eg, naphthalene, anthracene, phenanthrene, etc.). One taken = base 6_ to 10 - A member of the aromatic carbocyclic ring. When indicated as,, as the case may be, the group may be unsubstituted or may be independently selected from the group of substituents listed in the following "Substitution" Or a plurality of substituents (preferably not more than 3 substituents) substituted. The substituted η square group includes a chain of a scented moiety (for example, a biphenyl group, a terphenyl group, a phenylnaphthyl group, etc.). Preferably, the aromatic moiety is substituted by U2 substituents independently selected from the group consisting of: (c, (C) (C) (10), aryl, heteroaryl, 3 to benzene, hetero; Worm, gas base, mercapto group, (Cl_C4) alkoxy group, aryloxy group, amine group, (Cl-c6m-based amine group, bis(Cl_C3) alkylamino group or amino carboxylic acid vinegar (ie '(Cl- C3) alkyl-hydrazine-C(0)-NH_), and more preferably, substituted by a substituent of (c(10)m or (μ) alkoxy. The aryl group may be substituted by the aromatic Any carbon-sheet in the ring system is connected to the chemical entity Or a portion. Similarly, an aryl fluorenyl group or an aryl methoxy group (ie, the aryl moiety (aromatic moiety) of the aryl group has the same definition on the disk. 114897.doc -14-200804398. An aryl" or "heteroaromatic ring" refers to an aromatic moiety (10) such as a base group or a (four) group which is at least one hetero atom (for example, oxygen, sulfur, nitrogen or a combination thereof) in the 5- to (tetra) aromatic ring. ...specification, ten bases, stilbenyl, thienyl, furyl, benzofuranyl, oxazolyl, imidazolyl, pyrenyl, triazinyl, (tetra)yl...pyridyl, (iv)yl... : a benzofluorenyl group, a base group, an iso(tetra)yl group, a benzothiophenyl group, a benzo group, a pendant group, etc. The heteroaromatic moiety may be composed of a single or fused ring system. A typical monoheteroaryl ring system a 5 to 6 ring comprising from 1 to 3 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, and the typical fused heteroaryl ring system comprises from 1 to 4 independently selected from the group consisting of oxygen, sulfur and nitrogen. a 9- to W-membered ring system of a hetero atom. When indicated as ''may be substituted as appropriate,' then the heteroaryl group may be unsubstituted and may be independently selected from the definition of "substituted" below. One or a eve of the group of substituents: a substituent (preferably not more than 3 substituents) is substituted. When substituted, the oxime moiety is preferably oxime or two substituents independently selected from the group consisting of Take, (Cl alkyl, (C2-C3) alkenyl, aryl, heteroaryl, 3_heterocyclic, bromine, prepared mussels_美: rat, moth, chaotic, meridin, (C〗-C4 Oxyl, aryl = yl h group, (CA) alkylamino group, bis-(Ci_c3) alkylamino group or amine earth formazan (ie, (Ci_C3) alkyl 〇弋 (〇) ΝΗ ΝΗ And, more preferably, or 2 unique ☆, glare/field, from (CVC4) alkyl, gas, fluorine, cyano, trans-C4) alkoxy 1 (Cl_C4) alkylamine Or a di-(C-C2)alkylamine-substituted earth-substituted 1-heteroaryl group can be carried out by any one of the aromatic ring system to a chemical group, a non-hydrazine linkage, or a hydrazine (for example, imidazole- 1-yl, imidazolyl, imidazolium-4-yl, indole saliva, fluorenyl, pyridin-2-yl, pyridine-3-yl, pyridyl, pyr 114897.doc -15- 200804398 pyridine-5-yl or pyridine base). a heteroaryl group similar to the above-mentioned definition of β p hetero-fragrance, and the heteroaryl group of the hetero-aryloxy group (i.e., (heteroaryl)_c(〇H)_) The term "mercapto" as used herein refers to a hydrogen, alkyl, radical, partially saturated or fully saturated heterocyclic ring; c fully saturated ring = group. For example, a fluorenyl group includes, for example, the following: , 曱 基, 醯 、, 乙: Γ = = (. ^ ^ ^ butyl butyl, pentyl thiol, hexyl thiol, guangsan. butyl acetyl group, etc.) -^ ri γ ^ 6) Carbonyl (for example, cyclopropyl amide 1 yl (tetra) 'cyclopentyl county, cyclohexyl group, etc.), heterozygous # 厌 base (for example, '(four) bite (four), bite _2 ketone collar, hexahydro. Than the base of the m-methyl group, tetrahydro-w base, etc.), sulfhydryl (such as benzamidine) and heteroaryl fluorenyl (for example, thiophenyl-2-yl, thiophenyl-3-yl " Fuganji_2_ several groups, cough base _3_ several groups, ih_ material base_2·(four), 1H__ base _3· county, benzo[b]thiophenyl winter rebel, etc.). In addition, the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl portions of the fluorenyl group may be each defined above. Any of the groups set forth. When indicated as "optionally substituted", the thiol group may be unsubstituted or, as the case may be, independently selected from the group consisting of the substituents listed below. Substituting one or more substituents (generally from 3 to 3 substituents), or the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl portions of the fluorenyl group may be preferably as described above, respectively. Replacement of the substituents of the better list. In particular, the term "substituted" is envisioned and allows for one or more substitutions as is known in the art. However, those skilled in the art will generally appreciate that such substituents should be selected to avoid adverse effects on the pharmacological properties of the compound. 114897.doc -16- 200804398 Or adversely interfere with the use of the drug. Suitable substituents for any of the groups defined above include (CVC6)alkyl, (C3-C7)cycloalkyl, (CVC6)alkenyl, (CVC6) alkylene, aryl, heteroaryl, 3- To 6-membered heterocyclic ring, halogen (such as chlorine, bromine, iodine and fluorine), cyano group, hydroxyl group, (Cl_C6) alkoxy group, aryloxy group, thiol group (sulfenyl group), (Ci-C6) sulfur-burning Base, arylsulfide, amine, mono- or di-(q-C6)alkylamino, quaternary ammonium, amine (Ci_C6) alkoxy, urethane (ie (Ci-CJ alkane) -OC(O)-NH-), hydroxy (c2_c6) alkylamino group, amine group (c^c: 6) alkylthio group, cyanoamine group, nitro group, (Ci_c6) carbamyl group, ketone (oxo), fluorenyl, ((VC6)alkyl-c〇2·, hydroxyethyl, glycidinyl, fluorenyl, fluorenyl, sulfonyl, sulfonyl, sulfinyl Sulfur (cvc6)alkyl-c(0)-, sulfur (Ci-c6)alkyl-C (V& combinations thereof. In a substituted combination (eg, substituted aryl (C)_C0) alkyl, In the case of ,) the aryl or the alkyl group may be substituted, or both the aryl group and the alkyl group may be substituted by one or more substituents (usually from 丨 to 3) Substituted for the case of a full dentate substitution. A carbocyclic or heterocyclic group substituted with an aryl or heteroaryl group may be a fused ring (eg, dihydrogenated benzyl, dichlorobenzopyranyl, dichloro n) The term "solvate" refers to a molecular complex of a compound represented by formula (1) and a pharmaceutically acceptable salt thereof and one or more solvent molecules. These solubilized knives are such Generally used in the field of medicine, it is known to be harmless to the recipients <columns such as water, ethanol and the like. The term, hydrate refers to a solvent in which the solvent molecules in the pot are water. 〃 m is acceptable "indicates that the substance or composition is chemically and/or poisoned to the eyebrows and is compatible with other ingredients including the formulation and/or treated with it. 114897.doc -17- 200804398 Milk animals are compatible. The term n is substantially pure By means of a compound having a purity greater than or equal to 99.0% (preferably greater than or equal to 99.2%, more preferably greater than or equal to 99.5%, optimally greater than or equal to 99.7%). The starting materials used in the materials are usually available from commercial sources (eg Aldrich Chemicals (Milwaukee, WI)) may be readily prepared by methods well known to those skilled in the art (e.g., as generally described by Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, pp. Volume 19, Wiley, New Y〇rk (edited from 1967 to 1999) or prepared by the method of Beilsteins Handbuch der organischen Chemie, 4, Aufl·Edit Springer-Verlag, Berlin (also available from Beilstein online database) ). Scheme I below summarizes the methods and key intermediates of the invention. For a more detailed description of the individual reaction steps, see the Examples section below.

Scheme I, prepared by reference to the procedures in the U.S. Patent. When starting with the starting material (Ia) by means of the compound of the formula (IV) which is described in the above patent publication No. 2005/010592, 114897.doc 200804398, which is an alkyl group (or a carboxyl protecting group), it is first familiar to them. It is well known to those skilled in the art that the conventional hydrolysis procedure will hydrolyze vinegar to the corresponding acid. For example, the buffer-protecting group can be removed by treating the vinegar with a proton (e.g., a metal hydroxide, such as a gas oxidative) in a proton, a chelating agent (e.g., ethanol). The 1,1'.subunityl(tetra) solution is then dissolved in a suitable solvent (e.g., acetone 'tetrafuran, acetonitrile, dichloromethane or ethyl acetate) at or near room:. This solution is then added to (iv) the intermediate ... at room temperature or: near room temperature, wherein (b) is called a suspension in a suitable solvent. Water is added to quench the reaction. When a water miscible solvent (e.g., acetone, tetrahydroanthracene, and acetonitrile) is used, the aqueous solutions I are directly precipitated from the reaction mixture; ^When using water: a bathing agent (for example, acetic acid or methylene chloride), the product usually does not dissolve in the mixture and remains dissolved in the organic solution. Therefore, it is necessary to concentrate the solvent to sink the product. Therefore, the water is miscible; when X is oxygen, the starting compound of the formula (I-a) can be prepared in the manner as described in the following (4). 4 wherein x is on: sulfur or nitrogen such as sulfhydryl. The barrier can also be used with the course::: 114897.doc -19- 200804398

(l-2c-1)

Scheme II

The starting materials (I-2a) and (I-2b) can be prepared by the procedure of U.S. Patent Publication No. 2005/010592, which is incorporated herein by reference. See also the representative examples of such preparations in the Examples section below. In general, a compound of formula (i_2a) can be coupled to a compound of formula 2b) by means of Mitsunobii reaction conditions. For example, an amine-protected compound of formula (I-2b-1) is added to the thiol-protected compound of formula (I-2a-1) in the presence of triphenylphosphine at about room temperature. In a solution of a polar solvent (for example, tetrahydrofuran, diethyl ether, dichloromethane or toluene). The propylene diazodicarboxylate is then added until it has cooled to about 〇. The mixture was then slowly warmed to about room temperature to complete the reaction. For a more detailed description, see the example section below. These protecting groups can then be removed by standard conditions typically used to remove the particular protecting group used. Feather:: For use in isolation and purification as is well known to those skilled in the art: techniques for isolating the compounds of the invention and/or related thereto may be included in the art and are well known to those skilled in the art. And use ordinary sucking and attaching agent) (household 1 type / member type chromatography (high liquid chromatography (HPLC), M (such as tannin) column chromatography and thin layer chromatography), recrystallization 114897.doc -20- 200804398 and the difference (ie liquid-liquid) extraction technique. The compounds can be separated by themselves or in the form of their salts, solvates and/or hydrates. 'Knife separation and use. In some cases, the free test is preferred. The term "free test" as used herein refers to an amine group having a - lone pair. The term "salt" refers to a sub-bond or Inorganic and organic salts of the compounds incorporated in the molecule as complex compounds. These salts can be used in situ during the final isolation and purification of the compound or by separately reacting and separating the compound with a suitable organic or inorganic acid or base. Prepared from the salt formed. Representative salts include hydrobromic acid Salt, hydrochloride, hydrocyanate, sulfate, sulfate, nitrate, acetate, trifluoroacetate, oxalate, benzenesulfonate, palmitate, pamoate, C Diacid salt, stearate, laurate, malate, borate, benzoate, |L acid salt, phosphate, hexahydrate, benzoate, f-phenyl tartaric acid Salt, acid salt, acid salt, maleate, fumarate, succinate, tartrate, naphthalate, sulfonate, glucoheptonate, lactobionate and lauryl sulfonate Acid salts and the like. Preferred salts include hydrochlorides, methanesulfonates and sulfonates. These salts may include alkali metals and alkaline earth metals (e.g., sodium, lithium, unloading, dancing, towns, and the like). a primary cation, and includes, but is not limited to, ammonium, tetramethylammonium, tetraethylammonium, decylamine, decylamine, tridecylamine, triethylamine, ethylamine, and the like, non-toxic Recorded, quaternary and amine cations. See, for example, Berge et al., J. 5W, 66, pp. 1-19 (1977). The interstitial) may contain an asymmetric or palm center; therefore, such compounds and intermediates may exist in different stereoisomeric forms (Example 114897.doc -21 - 200804398 eg 'enantiomers and diastereoisomers The presence of all stereoisomeric forms of such intermediates and compounds, as well as mixtures thereof including racemic mixtures, are intended to form part of the present invention. The compounds prepared by the process of the invention may exist in a non-solvated form. It may also be in a form compatible with a pharmaceutically acceptable solvent (e.g., water, ethanol, and the like), and the invention is intended to cover both the compounded and non-column forms of the compounds. A list of pharmaceutically acceptable solvents Available from Center f〇r Drug Evaluation and Research (CDER) of the United States Federal Drug Administration (FDA)?

Washington DC was acquired. There are also intermediates and compounds such as may be in different tautomeric forms ▲ and all such forms are encompassed within the scope of the invention. The term "intertext" (construct or tautomeric form) refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton-shifting tautomers) include isomerization via proton interactions such as keto-enol and imine-enamine. Proton interconversions The specific example of a conformation is the part in which the feron can migrate between two ring nitrogens. The valence tautomers include recombination of electrons by some bonding electrons.

The invention also encompasses #田么τ< η , I , , , and isotopically labeled compounds (including intermediates) 'except one or more atoms consisting of a φ ^ θ atom or a mass number different from the common atomic mass in nature or In the case of the number of masses, the number of atoms, and the number of atoms, the compounds are described in this article. Examples of isotopes which can be incorporated into the intermediates or compounds of the present invention are: iridium, sulphur, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine 114897.doc -22·200804398 and gas isotopes, for example, 2h, respectively 3h, hc, " 1 3" 1r ... C 32η . 35 ( 13N, 15N, 15〇, 17〇, 18〇, 3ip and 36C1 13,

'C 18F, 123I, 125. Certain isotopically-labeled compounds (eg, such users) can be used for compound and/or substrate tissue distribution. X-isotope is easy to prepare and detect because of its::::: = = use of certain therapeutic advantages such as gas (ie, such as the addition of heavier isotopes to provide stability from the metabolism of the shirt (for example, live sputum, Ω ding period increase or agent / (10) therefore in some In some cases, it may be preferred. Isotopes (for example, 50, 13n, &quot;c and 18f) can be used in positive electrogram () studies to determine the substrate acceptor conditions. By the same: xin = = = often borrow The following procedures similar to those disclosed in the above schemes and /5 Examples are prepared by substituting a reagent which has not been isotopically labeled with a reagent, and the compound of the invention has been prepared by the method of the invention. Used in the treatment of diseases, disorders and disorders regulated by anti-drugs. ^Phase &amp; Preliminary studies have shown that the following diseases receptor antagonism __: _ disorders _ by marijuana vegetarian eclipse, anorexia and violence control (eg Calorie or food intake is reduced, and / Jing 2: Erguang fat, (four) disease, SARS Type "symptoms, biphasic borrowing early: psychosis, schizophrenia, behavioral sputum, inhibition related to reward (such as conditional site avoidance, inhibition of induced conditional location preferences), medicine, impulsive 秄A ^, Wood milk/dish, sputum disease, winemaking (eg alcohol abuse, cancer and/or dependence, including 阙114897.doc -23- 200804398 for prohibition, loss of desire and treatment for relapse prevention of alcohol intake), tobacco abuse (eg smoking addiction, cessation and/or dependence, including treatment for loss of desire and prevention of recurrence of smoking), dementia (including amnesia, Alzheimefs' disease, Alzheimer's disease, vascular dementia, Mild cognitive impairment, age-related cognitive decline and mild neurocognitive impairment), male sexual dysfunction (eg, erectile dysfunction), seizures, epilepsy, inflammation, gastrointestinal disorders (eg, gastrointestinal motility or intestinal propulsion) Dysfunction), attention deficit disorder (including ADD of attention deficit hyperactivity disorder (ADHD)), Parkinson's disease and type 2 diabetes. The present invention is not limited to the specific details of the examples, and other various modifications of the embodiments will be apparent to those skilled in the <RTIgt; In particular, other compounds of formula (I) can be prepared from the starting materials described in U.S. Patent Publication No. 2005/0101592, the disclosure of which is incorporated herein by reference. EXAMPLES Unless otherwise stated, starting materials are typically obtained from commercial sources such as Aldrich Chemicals (Milwaukee, WI), Lancaster Synthesis (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Co., Ltd. (Cornwall , England), Tyger Scientific (Princeton, NJ) and AstraZeneca Pharmaceuticals (London, England) o General experimental procedure at room temperature in a Varian UnityTM 400 or 500 (available from Varian, 114897.doc -24-200804398, Pal 〇Alt〇, CA) waking R spectra at 400 and 500 MHz respectively. The chemical shift is expressed in parts per million (8) relative to the residual solvent as an internal standard. The peak shape is expressed as follows: s, single peak; d, double peak · t one heavy peak, q quadruple peak; m, multiple peak; brs, broad single peak; s, extremely broad branch; br m, wide multiplet; 2s, Double single peak. In some cases, only representative 1H NMR peaks are given. The mass spectrometry was performed by direct flow analysis using positive and negative atmospheric pressure chemical ionization (APcI) scanning modes. Use a Gils〇n 2丨5 liquid handling system

Waters APcI/MS type ZMD mass spectrometers were used to perform these experiments. Mass spectrometry was also obtained by an RP_HPLC gradient method for chromatographic separation. The molecular weight markers were recorded by positive and negative electrospray ionization (ESI) scan mode. The experiments were carried out using a Waters/Micromass ESI/MS type ZMD or LCZ mass spectrometer equipped with a Gilson 215 liquid handling system and Hp 11 〇〇 DAD. When clarifying the intensity of ions containing gas or bromine, the expected intensity ratio (about 3 Å for ions containing 35C1/37C1 and ι:1 for ions containing 79Br/81Br) is observed and only given Lower mass ions. Report the MS peaks for all instances. The optical rotation was measured at a specified temperature using a sodium D line (λ = 589 nm) on a PerkinElmerTM 241 Polarimeter (available from PerkinElmei Co., Wellesley, MA) and recorded as follows: [0〇, 叩, concentration (c = g / 1 ml) and solvent. Use BakerTM Silicone (4 μm, JT Baker, phiUipsburg, NJ) or Silicone 50 (EM SciencesTM, Gibbstown, NJ) on a glass column or at 114897.doc -25- 200804398

Bi〇tageTM column (ISC, sheh〇n, CT) κ fine ί column chromatography under low nitrogen pressure. Radial chromatography was performed with the help of chromatotronTM (Harrison Research). Starting Materials / Intermediates The reagents used in the following preparations and various starting materials are available from commercial suppliers such as Sigma-Aldrich (Milwaukee, WI USA) starting material 2,2-difluoro-propionic acid ethyl ester Preparation of (1·3α)··

3 (I_3a) Trifluoro(diethylamino)sulfide (125 g, 780 mmol) was added dropwise to a stirred cold (〇.〇) ethyl pyruvate (71 mL, 650 mmol) in. The reaction was allowed to warm to ambient temperature overnight then quenched by slowly poured onto ice/water mixture and extracted with diethyl ether. The organic phase was washed with brine, dried (Naj.sub.4) and concentrated in vacuo. The oil obtained was subjected to fractional distillation under an ambient pressure (m.p. ° Preparation of intermediate 2,2-difluoro 4-(2-hydroxy-ethyl)-propanamide (ία): 〇

(I-3b) 2,2·difluoro-propionic acid ethyl ester I-3a (10.1 g, 70 mmol) was added dropwise to the stirred cold (0. 〇ethanolamine (4_4 mL, 70 mmol) The title compound (I_3b) (112 g) was obtained as a solid. mp. Preparation of 2-mono-1-propylaminodiethanol (uc):

Ch3 Ηα (Ι·3ο〇 was added dropwise to a stirred solution of lithium aluminum hydride (5·5 g, 146 mmol) dissolved in diethyl ether (85 ml) at a ratio that kept gentle reflux. 2,2 a solution of di-oxo-indole-(2-trans-ethyl-ethyl)-propionamide (1) 2 g, 73 mmoles dissolved in diethyl ether (ml). After an additional 15 hours, the reaction was quenched with sodium sulfate decahydrate and diluted with ethyl acetate and allowed to stir for 18 hours. By means of Shi Xi, (4) the mixture was washed with acetic acid. Concentrate in a vacuum Λ; consider the liquid and enter the d-class steaming plant (1), and collect the steaming house in the order of the column to obtain the title compound (four) in the colorless oil). The preparation of the starting intermediate 5·(4·chlorophenyl)·W2_gasphenyl)_4-permeate, 1 Η-port is more than -3-, 7 Λ匕, 丄τ ® owes Two different ways of ethyl ester (referred to herein as Ma-4 and Ma_7). Preparation of intermediate 4 -5 - (4 · gas stupid base [π gas phenyl)_n ton of formic acid acetonitrile (1-1 a-1): 114897.doc •27- 200804398

(I-1 a-1) Add O (15 ml, 294 mmoles to 5•(4) gas phenyl) small (2-chlorophenyl)-1Η-pyrazole-3·carboxylate ( 2.6 g, 73·6 mmoles in a cooled (ice/water bath) stirred solution in acetic acid (300 mL). After 45 minutes, the reaction was concentrated in EtOAc (EtOAc). Heart 1) (29.6 g). Preparation of intermediate 5-(4-phenylphenyl phenylvinyl-1-indole-pyrazolecarboxylate (1-1 a·2):

(Ma-2) Ethyl bromide-5-4-phenylphenyl)-1-(2-chlorophenylpyrazole-3-carboxylate ethyl ester 1-1 a-1 (5 · 2 g ' u 9 mmol) Ear), tributylvinyltin (7·〇 ml, 23·8 Amor) and triphenylphosphine palladium (0.7 g, 〇·6 mmol) dissolved in 114897.doc -28- 200804398 DMF The solution in (12 ml) was heated at 110 ° C for 18 hours. The black solution was allowed to cool 'distributed between B/water, the organic layer was washed with brine, dried (NazSCU) and dried in vacuo. Concentration to give a semi-solid. The title compound (I-la-2) (3.0 g) was obtained as a white solid. Preparation of ethyl-1-(2-phenylphenyl)-4-carbamido-1H-pyrazole-3-carboxylate (1-1α-3):

(I-la-3) Ginger vacuum drying to give a brown solid to give 5-(4-chlorophenyl)-bu(2-chlorophenyl)-4-vinyl-iH-u to jun-3- Ethyl formate Ma-2 (2.9 g, 7.5 mmol), iron tetraoxide (8 mg, 〇〇8 mmol) and N-methylmorphine oxide (1.1 g, 8.2 mmol) The solution in dioxane hexane (24 ml) / water (6 ml) was stirred at ambient temperature for 18 h then sodium periodate (16 g, 75 mmol) was added and stirring was continued. hour. The thick slurry was diluted with ethyl acetate (100 mL), filtered and washed twice with EtOAc. The combined filtrates were solidly washed with water and brine, dried (NajO4) and concentrated in a vacuum to give a solid material. The solids were slurried in hot hexanes (3 mL), cooled, filtered and then applied to &lt;RTIgt;&lt;/RTI&gt; Preparation of 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-hydroxypyrazole a. formic acid ethyl ester (Ι-1α-4):

(I-la-4) to 5-(4-chlorophenyl)-1-(2-indolyl)_4-mercapto-1H_pyrazole-3-carboxylate Ι-1α-3 (2 2 g, 5.6 mmol (m 2 ) of methane perbenzoic acid (2.9 g (5 〇% purity), 8.4 mmol) dissolved in a stirred solution of di-methane (22 ml) and stirred The resulting slurry was allowed to stand for 6 hours. The mixture was diluted with EtOAc (EtOAc m.) Triethylamine (1 ml) was added to a slurry of this material in methanol (20 mL) to yield a solution. After 45 minutes, the reaction was concentrated in vacuo to give a color solid. The material was purified by EtOAc (EtOAc EtOAc (EtOAc) ) (1.5 grams). An alternative procedure for the preparation of the intermediate 5-(4-chlorophenyl)-1-(2·chlorophenylhydroxypyrazolecarboxylic acid ethyl ester (I-la-4) is described below. Intermediate 4 · Preparation of chlorinated base + oxo-butyric acid B_7-5): 114897.doc -30- 200804398

(I-la-5) Add triethylamine (58.7 kg / 580 mol) and magnesium dichloride (23 2 kg / 244 mol) to the malonate B dissolved in 2-methyltetrahydrofuran (73 gallons) Ester potassium salt (4 丨. 5 kg / 244 m). The mixture was heated to 6 Torr. In a separate vessel, 4-methoxyphenylacetic acid (19.8 kg / 116 mol) dissolved in tetrahydrofuran (21 gallons) was added to 1,1,-carbonyldiimidazole (198 kg / 122 mol). In a suspension in tetrahydrofuran (37 gallons). The activated thiol (iv) reaction mixture was added to the prepared malonate mixture at 6 Torr (&gt;c and held for 2 hours. After the reaction mixture was cooled to ambient temperature, an aqueous citric acid solution (96 kg) was added. /5 〇〇mol, dissolved in 9 〇 gallons of water) to achieve a few reactions. After the j wash with citric acid aqueous solution and two washes with aqueous sodium bicarbonate to remove all salts and unreacted reagents The two products 3 were placed in the organic layer. The organic layer (tetrahydrofuran and methyl tetrahydrofuran mixture) was concentrated under vacuum and replaced with 2B ethanol. Then the knife was separated from 2B ethanol ( Preparation of the title compound in the form of a solution in 24 gallons) of butyrate B intermediate 4·(4-Phenylphenyl)_2_[(2-chlorophenyl)-indenyl]oxopurine (1-1 α_6) ···114897.doc -31 - 200804398

2-Chloroaniline (14.1 kg / 11 Torr) was dissolved in a mixture of water (34 gallons) and 2]8 ethanol (41 gallons). The solution was cooled to dryness and then treated with a 35% aqueous solution of hydrochloric acid (32·1 kg / 3 〇 7 m). Add 97% aqueous sodium nitrite (7.9 kg / 110 mol, dissolved in 4 gallons of water) and then aqueous sodium acetate (27.1 kg / 331 m, dissolved in 21 gallons of water) to the aniline hydrochloride mixture. Forming a diazo intermediate. Compound Ma_5 (from above) dissolved in 2 Β ethanol was then added and the reaction was allowed to warm to ambient temperature, triturated and filtered. The cake of the title compound (I_la_6) was washed once with water (8 gallons) and 4 times with 2B ethanol (8 gallons per wash). The ethanol wash removes most of the dark orange material leaving a yellow solid. After drying overnight in a vacuum oven, 4 〇 kg (91 理论 of theory) of title compound was recovered. Preparation of intermediate 5-(4-phenylphenylchlorophenyl)_4•hydroxy-ΐΗ_σpyrazolic acid ethyl ester (I-la-7): 114897.doc -32- 200804398

(I-la-7) Add a solution of Sanxi acridine (18 2 kg / 512 mol) dissolved in tetrahydrofuran (42 gallons) to tetrahydrofuran (33 gallons; intermediate Ma in ambient temperature) -6 (18 kg / 47 · 5 m). Add carbonated aqueous solution of sodium chloride / ΗΜ mol, dissolved in 3 〇 plus residual water) and sulfite (4) aqueous solution (10) kg / 47.5 mol, dissolved in 18 gallons of water ). The mixture was allowed to give 4 hours to complete the cyclization to give the pyrazole. The initial phase separation was first carried out and then the aqueous layer was extracted with ethylene diacetate (24 additional). Combine the acetic acid and the tetrahydrogenate extract with an aqueous solution of citric acid (182 kg / 94.9 m, dissolved in 20 gallons of water) and an aqueous solution of sodium chloride (24 kg / 41 丨 mol, dissolved in μ Add the water to the knee). The organic layer was hanked under vacuum, and the mixed solvent was completely replaced with 2-propanol. After 4 hours of granulation, the title compound (1-7) was obtained as a yellow &amp; solid from the mixture and washed with 2-propanol (6 liters). After drying in a vacuum oven for 2 days, the yield was 13.6 kg (76/% of theory). The title compound (I_la_7) is the same as the compound ι_la-4 produced above. EXAMPLES Steroids (3 (ethoxycarbonyl)]·(2_chlorophenylbu 5·(4-chlorophenylbisazolyloxy)ethyl 2,2-difluoropropylaminocarboxylic acid third- Preparation of butyl ester (1 Yang 114897.doc -33- 200804398 8):

(I-la-8) A solution of di-tert-butyl dicarbonate (15.5 kg / 70.9 mol) dissolved in tetrahydrofuran (7 gallons) over 1 hour was added to 2-(2,2-difluoro-propane Ethylamino)-ethanol (I-3c: 9.1 kg/64.4 mol) was dissolved in 4 (rc solution) in tetrahydrofuran (7 gallons). After 2 hours, the reaction was allowed to cool and kept at 2 (rc The solution was then stirred overnight. The solution was then added to triphenylphosphine 丨.3 kg / 80.5 mol) and 5-(4-phenylphenyl phenyl)_4 hydroxy oxazol-3-carboxylic acid Ethyl ester (Ma-7 ····················································································· Diisopropyl formate (16·3 kg / 8 〇·5 mol). The reaction was allowed to continue at 〇 ° C for an hour and then warmed to 2 ° C over 9 Torr. The mixture was allowed to dry under vacuum. Concentrate until 3 gallons remained. Add 2 -propanol (55 gallons) and concentrate the mixture at atmospheric pressure to distill the remaining tetrahydrofuran. Reheat the reaction mixture and let it under 75 in 2-propanol (95 gallons) Hold for 1 hour, then cool and keep at 20 ° C. Use the crystal from the sample 114897.doc -34- 200804398 to sample the crystals to induce the crystallization of the batch. After stirring overnight, filter the 4 solids and use 2 - Cesarean* 乂 s (16 gallons) was washed. After drying in a vacuum oven for 2 days, 29.9 kg of the title compound (I-la-8) (77% yield) was recovered. lHNMR (4 〇 ° ^ D6) 5ppml, (m?12H)1, (called 3-H) 3·4 (m, 2 H) 3·6 (t, 7 is 3.7, 2 H) 4.G (m, 2 Η) 4· 3 J 7·3' 2 H) 7·2 (m, 2 H) 7·4 (d,8·1,2 Η) 7.5 (m 3 Η) 7.7 (m,l Η) , 4-(2- (2) -2 propylamine, #土)oxy)-1-(2-lactylphenyl)-5-(4-chlorobenzophenone) 1H than 嗤i formic acid hydrogenate 〇7_9) Preparation:

The solution of potassium oxidized potassium (2.8 kg, 5 〇 3 mol) dissolved in water (10) was added to Ma, 25" kg / 41 9 m) in 30 minutes, dissolved in 2B ethanol (17 gallons) and 2 _Methyltetrahydrofuran (33 gallons) in solution. The hydrolysis as determined by HPLC analysis was completed in 4 hours. The concentrated chlorous acid (6.4 kg / 90.6 mol) dissolved in water (46 liters) added in (four) minutes should be dissolved in the night. The mixture was diluted with 2-methyltetrahydrofuran (17 gallons) and the phases were separated. _Water_Financial layer and concentrated under vacuum to about 114897.doc -35- 200804398 33 plus life. Concentration of 35% hydrogen acid (12. 8 kg / 181.2 mol) was added and this was done. Heat to 60 °C. The reaction was judged to be 99.5% complete at 60 hours and allowed to cool to 2 Torr. The mixture was diluted with 2·decyltetrahydrofuran gallon and concentrated under vacuum until about 66 gallons remained. To remove residual water in the form of a di-bath, the concentrated mixture was heated and concentrated under atmospheric pressure until about 33 gallons remained. This dilution and concentration step was repeated because no crystals were apparent during cooling. 2-Methyltetrafuran (95 gallons) was added and the mixture was concentrated under atmospheric pressure until about 33 gallons remained. Cool to 2 〇. The desired product was crystallized from the mixture upon hydrazine and filtered after granulation for 2 hours. The solids were washed with 2-methyltetrahydrofuran (13 gallons) and dried in a Hastelloy pan dryer at 4 ° C for 15 hours. The title compound (I-la-9) was isolated in 90% yield (B). ]H NMR (400 MHz? DMS0-D6) δ ppm 1.7 (t5 J.l9 5 Hz? 3 H) 3.3 (t5 Hz? 2 H) 3.6 (t5 J=14.7 Hz, 2 H) 4.3 (t ^=5.2 Hz? 2 H) 7.3 (d? /=8.3 Hz5 2 H) 7.4 (d? J=8.3 Hz 2 H) 7.5 (m,3 H) 7.7 (dd, J=7.15 2.1 Hz, 1 H) From Intermediate (I-la-9) Preparation of 3-(4-chloro-phenyl)·2_(2_qi-phenyl)_?_(2,2-difluoro-propyl)-6J-dihydro-2H,5H -4-oxa-L2,7_s aza-chamomile ring -8 ketone (IA-1): 114897.doc -36- 200804398

A solution of 1, hydrazine-carbonyldiimidazole (10.6 kg / 65.3 mol) in acetone (40 gallons) was added to acetone (37.7 mol) at 20 C for 90 minutes in acetone (25 gallons). In the suspension. After 1 hour, the reaction was determined to be about 88% complete by HPLC analysis. After the addition of 1 hour, the reaction was completed more than 99%. Water (110 gallons) was added to the mixture over a period of 90 minutes at 20 °C. The resulting slurry was stirred at 2 ° C for 14 hours and at 5 ° C for 90 minutes. The filtered solid was washed with water (5 gallons) and dried under a stream of nitrogen for only 1 hour to obtain 2 〇·7 kg of wet solid. The wet cake from above was used directly for recrystallization without storage. The yield is assumed to be 100% for the purpose of the calculation. A solution of IA-1 (assuming 17.1 kg / 37.7 mol) dissolved in acetone (27 gallons) was filtered through a 微米 5 μm filter. Filtered water (54 gallons) was added to the acetone solution over 30 minutes at 20 °C. The resulting slurry was stirred at 2 CTC for 17 hours. The mixture was cooled to 5 over an hour. (: and kept at this temperature for an additional 3 hours. Filter this &amp; and wash with filtered water (3 · 〇 life). Dry the separated solids at 40 C for 2.5 days to get 15·3 Kilogram ia-1 (90% yield). II4897.doc -37- 200804398 The purity of the product is now 99·70/〇. Powder X-ray diffraction (PXRD: Bruker D5000) and polarized light microscopy (PLM) analysis It was confirmed that the separated compound was completely crystallized at a starting temperature of 30.00 ° C and a final temperature of 300.00 ° C using a differential scanning calorimetry (DSC; Mettler-Toledo 822e), and the melting onset temperature was found to be about 156. °C. The PXRD pattern shown in Figure 1 was produced by means of a Bruker D500 X-ray powder diffractometer under the following conditions.

Start: 3 Stop: 40 Steps: 0.04 Time/Step: 1.0 second Scan mode: Continuous generator: 40 kV, 30 mA Radiation: Copper Κα (fine focus X-ray tube) Divergence slit: 1 mm scattering slit: 1 mm receiving slit: 0.6 mm detector: Kevex PSI [Simplified illustration] Figure 1 illustrates 3_(4-chloro-phenyl)_ 2-(2' chloro-phenyl) synthesized by the method described herein a powder of 7-(2,2-difluoro-propyl)-6,7-dihydro-2η,5η_4-oxa-I2,7-triaza-chamomile-8-one (IA-1) Ray diffraction. 114897.doc -38-

Claims (1)

200804398 Scope of application: A method for preparing a compound of the formula (1), a salt which is more acceptable than a servant, or a solvate or a hydrate of the compound: Wherein A is nitrogen and B is carbon, or A is carbon and B is nitrogen; R〇a, R〇b, la 匕 are each independently halogen, ((VC4) alkoxylate, (Ci-CU) alkyl, (CrC4) alkyl or cyano group; η and m are each independently ;; X system 0, S, S〇, Qn, 2a 2, -N(R a)- or ~C(R2b) (R2c)-, wherein each of R a, R21 ^ r2c is a wind, (C1-C4) alkyl, halogen-substituted (Cl-C4) or (c)-c5) fluorenyl; R3b is independent Hydrogen, (Ci_C6) alkyl or substituted (cvc6) alkyl, or 113 &amp; or 1131) and R4 one by one - open y into a monovalent or partially saturated 5 · to 6-membered heterogeneous ring, where ^ The τ Zuo-Feng, ^ 裱 裱 、 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可 可Chemical group of the following constituents: ((iv))alkyl, 114897.doc 200804398 aryl, heteroaryl, aryl (Ci_c4) alkyl, saturated carbocyclic, heteroaryl (Cl_C3) alkyl, 5 Indoleamine and 3 - w _ , 3- to 8-membered partially or completely 5 to 6-membered lactone, 5- to 6-membered b heterocyclic ring, of which the chemical department a heterocyclic ring, a heterocyclic ring thereof, wherein the heterocyclic ring may optionally contain additional heteroatoms of the orchard and may optionally be saturated with one or all or part of the 5 to 6 member states. From oxygen, nitrogen "takes one or more substituents including the following steps: 〇) cyclizes a compound of formula (I-a) in the presence of 1,1,-diyldimethicin to produce a compound of formula (1) Wherein R is hydrogen; and A, B, R0a, R〇b, Rla, Rib, n, m, X, R3a, R3b &amp; R4 are as defined above; and (2) isolating the compound of formula (I), its medicinal An acceptable salt or a hydrate or solvate of the compound or the salt. 2. The method of claim 1, wherein the cyclization step (1) is carried out in a water miscible solvent. 3. The method of claim 1 or 2, wherein a is nitrogen, B is carbon, X is oxygen and R3, 114897.doc 200804398 and R3b are both hydrogen. 4. The method of claim 3, wherein R4 is selected from the group consisting of (Ci_C8) alkyl, aryl (Ci-C4) alkyl, 3- to 8-membered or fully saturated carbocyclic, and up to 8-membered partially or completely a chemical moiety of a group of saturated heterocyclic rings, wherein the chemical moiety may be optionally substituted with one or more substituents, or R together with R or R3b form a complete or partial saturation to a 6-membered %, wherein the heterocyclic ring The ring may be substituted by one or more substituents as appropriate. 5. The method of claim 4, wherein the R4 is a (CrC8) alkyl group, a cyano substituted (CVC8) alkyl group, a cyclopentyl group, a cyclohexyl group, a hexahydropyridine small group, a pyrhabitan-1-yl group or琳琳-丨_基. 6. The method of claim 5, wherein R, 2, 2_di-propyl. Ί· One kind of preparation for 3xing 4-gas-benzene,? . ^ — 1 gas base) 1 (2-[phenyl)-7-(2,2-difluoro-propyl)_6,7-dihydro-2H,5H-4-oxa! 0 1 A method of producing 1, 2, 7-diaza-chamomile ring-8-酉, which comprises the following steps: (1) sitting in 1H carbon-based two-meter rice, in the presence of ^ΠΑ Cyclizing a compound of formula (Ma) to produce a compound of formula (IA-1) (Ma) 114897.doc 200804398 and (2) isolating the compound of the formula (ΙΑ-1) or a hydrate or solvate of the compound. 8. The method of claim 7, wherein the cyclization step (1) is in the form of a water-miscible solvent, or the method of claim 7 or 8, wherein the compound of the formula 1-1 a is by the following Wherein G) is prepared by coupling a compound of formula (1-2a-1) with a compound of formula (I-2b-1) to yield a compound of formula (I-2cM) CI (I-2C-1) wherein Pgi is a carboxy protecting group and a Pg2 is an amine protecting group; and (11) removing the group-protecting group (Pgl) and the amine-protecting group (Pg2) ) to produce the compound of formula (I-la). Οο-3_(4_Chloro-phenyl•chloro-phenyl):-7-(2,2-difluoro-propyldihydro-2Η,5Η_4·oxygen prepared by the method of claim 8 Crystalline type of heterodiazepine-chamomile ketone. 11. 3-(4-chloro-phenyl)_(gas-based)-7-(2,2) having the X-ray diffraction pattern illustrated in Figure 1. -Fluoro-propyl)-6,7-dihydro-2^15511-4-oxa-1,2,7-diaza-carnation ring n is substantially pure crystalline. 114897.doc