HK1029345B

HK1029345B - Polymorphic form of the tachykinin receptor antagonist 2-(r)-(1-(r)-(3,5-bis(trifluoromethyl) phenyl)ethoxy)-3(s)-(4-fluoro) phenyl-4-(3-5(-oxo-1h,4h-1,2,4,-triazolo) methylmorpholine

Info

Publication number: HK1029345B
Application number: HK01100223.8A
Authority: HK
Inventors: L‧克罗克; J‧麦考利
Original assignee: Merck Sharp & Dohme Corp.
Priority date: 1997-07-02
Filing date: 1998-07-01
Publication date: 2004-02-06

Description

Crystalline forms of the tachykinin receptor antagonist 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine

Summary of the invention

The invention relates to a novel crystal form compound 2(R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine.

The invention also relates to pharmaceutical preparations containing the novel crystal form compound as an active ingredient, and application of the compound and the preparations thereof in treating certain diseases.

The novel crystalline forms of the present invention are tachykinin receptor antagonists useful in the treatment or prevention of central nervous system disorders, inflammation, pain or migraine, asthma and emesis.

The crystalline forms of the present invention have advantages in terms of thermodynamic stability and suitability for use in pharmaceutical formulations compared to other known forms of 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine.

Background

Neuropeptide receptor of substance PThe body (neurokinin-1; NK-1) is widely distributed in the mammalian nervous system (especially the brain and spinal ganglia), circulatory system and peripheral tissues (especially the duodenum and jejunum) and is involved in regulating many different biological processes. This includes perception of olfactory, visual, auditory and painful sensations, motor control, gastric motility, vasodilation, salivation and urination. Substance P (also referred to herein as "SP") belongs to the naturally occurring undecapeptide of the tachykinin type, which is so-called because it rapidly promotes the contraction of extravascular smooth muscle tissue. Tachykinin is based on the remaining carboxy-terminal series Phe-X-Gly-Leu-Met-NH₂A distinction is made. In addition to SP, known mammalian tachykinins include neurokinin a and neurokinin B. The generic names NK-1, NK-2 and NK-3 represent the receptors for SP, neurokinin A and neurokinin B, respectively.

Substance P is a pharmaceutically active neuropeptide produced in mammals which acts as a vasodilator, an inhibitor, a stimulator of salivary secretion and produces an increase in capillary permeability. It can also produce analgesia and hyperalgesia in animals, depending on the dose and the pain responsiveness of the animal.

The use of tachykinin receptor antagonists in pain, headache (especially migraine), alzheimer's disease, multiple sclerosis, morphine withdrawal symptoms, cardiovascular changes, edema (such as that caused by thermal injury), chronic inflammation (such as rheumatoid arthritis), asthma/bronchial hyperreactivity and other respiratory diseases (including allergic rhinitis), gut inflammation (including ulcerative colitis and Chrohn's disease), eye injury and inflammation, proliferative vitreoretinopathy, irritable bowel syndrome and bladder function disorders (including cystitis and detrusor hyperreflexia) has been described.

It has also been proposed that tachykinin receptor antagonists may also be useful in the following diseases: depression, dysthymia, chronic obstructive airways disease, hypersensitive diseases (e.g. to poison ivy), vasospastic diseases (e.g. angina and reynaud's disease), fibrous and collagenous diseases (e.g. scleroderma and eosinophilic fascioliasis), reflex sympathetic dystrophy (e.g. shoulder/hand syndrome), addiction diseases (e.g. alcoholism), stress-related body segment diseases, neuropathy, neuralgia, diseases associated with immune enhancement or inhibition (e.g. systemic lupus erythematosus), ophthalmic diseases (e.g. conjunctivitis, vernal conjunctivitis, etc.), skin diseases (e.g. contact dermatitis, atopic dermatitis, respectful measles and other eczematoid dermatitis).

Various efforts have been made to provide substance P and other tachykinin receptor antagonists in order to more effectively treat the various conditions and diseases described above. Certain morpholine and thiomorpholine compounds are disclosed as substance P antagonists in PCT publication WO94/00440, EPO publication 0,577,394, and PCT publication WO 95/16679. In particular, the compound 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine has been disclosed as the title compound of example 75 of PCT publication WO 95/16679.

The morphology of the pharmaceutical compound is important in that it involves the study of a suitable dosage form because the exact dosage applied and measured in one lot is not consistently compared to another if the morphology of the compound is not kept constant during clinical and stability studies. Once a pharmaceutical compound is used as a product, it is important to know the crystal form of the compound used in each dosage form in order to ensure that the same form of drug is used in the manufacturing process and that the same dose of drug is contained in each dosage form. It is therefore absolutely necessary to ensure that the compound is in a single crystalline form or a known mixture of some crystalline forms. Furthermore, certain crystalline forms may have increased thermodynamic stability in pharmaceutical formulations and are therefore more suitable than other crystalline forms. Polymorphic compounds in the present application have the same chemical structure, but in a different crystalline arrangement.

Drawings

FIG. 1 is a powder X-ray diffraction pattern of form I2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine.

FIG. 2 is a powder X-ray diffraction pattern of form II 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine.

Detailed description of the invention

The present invention relates to a novel crystalline form of the compound 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine and a process for preparing the crystalline form.

The compound 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine has the following formula,it is a tachykinin receptor antagonist useful in the treatment of inflammation, pain or migraine, asthma and emesis,

this particular crystalline form (referred to herein as form I) has superior properties compared to other crystalline forms of the compound, is thermodynamically more stable than other crystalline forms, and is therefore more suitable for inclusion in pharmaceutical formulations.

The invention also relates to a process for preparing 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine form I, which comprises

Form II 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine is equilibrated in a solvent selected from the group consisting of ethanol, 2-propanol, acetonitrile and isopropyl acetate.

Heating a sample of 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine with optional morphological composition to 215-230 ℃, and then heating

The sample was returned to room temperature.

In particular, heating 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine can be carried out in an open pan under a nitrogen atmosphere in a differential scanning calorimeter cell, and 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine can be heated to about 215-230 ℃, then cooled to room temperature. Preferably, the starting form of 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine is form II.

In addition, the present invention relates to another process for the large scale preparation of form I2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine, which comprises

Suspending 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine, optionally in morphological form, in methanol/water solution (preferably in the ratio 2/1V/V);

adding seed crystals of form I2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine;

the resulting mixture is stirred at about 0-50 ℃ for a period of time sufficient to form 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine form I, and

collecting the formed form I2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine.

Likewise, the present invention also relates to a process for preparing morphologically homogeneous 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine comprising any of the methods described above.

The novel crystalline forms of the compounds of the present invention, 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine, are tachykinin receptor antagonists useful in the treatment of inflammation, pain or migraine, asthma and emesis.

Form I2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine is anhydrous and non-hygroscopic and has a high degree of thermal stability as a pure solid and in hydroalcoholic solution.

Form II is an anhydrous crystalline material having a melting point of 254 ℃ and is obtainable directly by recrystallization from the chemical synthesis of 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine.Powder X-ray diffraction (XRPD)

Powder X-ray diffraction studies have been widely used to elucidate molecular structures, crystallization and polymorphism. Powder X-rays (XRPD) were recorded using a Philips APD 3720 powder diffractometer equipped with a 3kw X-ray generator (CuK α 1 radiation) and a NaI (Ti) scintillation detector. The samples were maintained at ambient temperature as measured from 3 ° to 45 ° (2 θ), and the results are shown in figures 1 and 2.

Form I2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine is characterized by a powder X-ray diffraction pattern having critical reflections at about 12.0, 15.3, 16.6, 17.0, 17.6, 19.4, 20.0, 21.9, 23.6, 23.8 and 24.8 ° (2 θ).

Form II 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine is characterized by a powder X-ray diffraction pattern having critical reflections at about 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9 and 24.8 ° (2 θ).

The XRPD patterns above confirm that the two samples have different crystalline forms. Both form I and form II have strong peaks characteristic of crystalline material.Differential scanning calorimetry [ DSC ]]

Differential scanning calorimetry of form I2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine and form II 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine showed that, both of the thermograms obtained at the same temperature have a single melting endotherm.

In particular, the Differential Scanning Calorimetry (DSC) curve of 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine form I shows a single melting endotherm with a peak temperature of 255.8 ℃, an extrapolated onset temperature of 254.7 ℃, and an enthalpy of 105J/g, whereas 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1 form II, the DSC curve of 2, 4-triazole) methylmorpholine also showed a single melting endotherm with a peak temperature of 255.6 deg.C, an extrapolated onset temperature of 254.4 deg.C, and an enthalpy of 107J/g.NMR

Proton and carbon nuclear magnetic resonance spectra of form I and II show that there is no chemical change in the conversion from form II to form I.DissolutionDegree of rotation

The solubility of form I was 0.9. + -. 0.1mg/ml as determined at 0 ℃ in 2/1(v/v) methanol/water. The solubility of form H was 1.3. + -. 0.2mg/ml as determined at 0 ℃ in 2/1(v/v) methanol/water. The ratio of solubilities was 1.4, indicating that form I is the more stable form. Form I is more stable (0.2kca/mol) than form II.Steam pressure

The vapor pressures of form I and form II were found to be the same at elevated temperatures when measured by knudsen escape techniques.

Tachykinin antagonism assay

The compound of the present invention, form I crystals of 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy-3- (S) - (4-fluoro) phenyl-4- (3- (5-fluoro-1H, 4H-1, 2, 4-triazole) methylmorphine, is effective in antagonizing tachykinins, particularly substance P and neurokinins, in the treatment of gastrointestinal disorders, central nervous system disorders, inflammation, pain or migraine, asthma and emesis in a mammal in need of such treatment.

A. Receptor expression in COS

In order to transiently express the cloned human neurokinin-1 receptor (NK1R) in COS, the cDNA for human NK1R was cloned into the expression vector pCDM9, which was obtained from pCDM 8(INVITROGEN) by inserting the ampicillin resistance gene (nucleotide 1973-2964 from BLVESCRIPT SK +) into the Sac II site. Using IBI GENEZAPPER (IBI, New Haven, CT), at 260V and 950. mu.F, in 800. mu.l transfection buffer (135mM NaCl, 1.2mM CaCl)₂，1.2mM MgCl₂，2.4mM K₂HPO₄，0.6mM KH₂PO₄10mM glucose, 10mM HEPES pH7.4), by means of electroporation, 20. mu.g of this plasmid DNA was transfected into 1 million COS cells. The cells were cultured in 10% fetal bovine serum, 2mM glutamine, 100U/ml penicillin-streptomycin, and 90% DMEM medium (GIBCO. GrandIsland, NY) at 37 ℃ with 5% CO₂The medium-cultured strain is cultured for 3 days,binding assays were then performed.

B. Stable expression in CHO

To establish a stable cell line expressing this clone human NK1R, the cDNA was subcloned into the vector pRcCMV (INVITROGEN), IBI GENEZAPPER (IBI), 300V and 950. mu.F, in 800. mu.l of transfection buffer supplemented with 0.625mg/ml herring sperm DNA, by means of electroporation, with the aim of transfecting 20. mu.g of this plasmid DNA into CHO cells. The transfected cells were cultured in CHO medium [ 10% fetal bovine serum, 100U/ml penicillin-streptomycin, 2mM glutamine, 1/500 hypoxanthine-thymidine (ATCC), 90% IMDM medium (JRH BIOSCIENCES, Lenexa, KS), 0.7mg/ml G418(GIBCO), 37 ℃, 5% CO₂Until colonies appear. Each colony was isolated and propagated. The cell clone with the highest number of human NK1R was selected for subsequent use such as drug screening.

C. Assay protocol Using COS or CHO

For COS or CHO cells expression of human NK1R binding test, based on¹²⁵I-P substances (A-P)¹²⁵I-SP, from DU PONT, Boston, MA) as a radiolabeled ligand that competes with unlabeled substance P or any other ligand for binding to human NK 1R. COS or CHO monolayer cultured cells were separated with a non-enzymatic solution (SPECIATY medium, Lavallate, NJ) and resuspended in an appropriate amount of binding buffer (50mM Tris pH7.5, 5mM MnCl)₂150mM NaCl, 0.04mg/ml bacitracin, 0.004mg/ml leupeptin, 0.2mg/ml BSA, 0.01mM phosphoramidite) so that 200. mu.l cell suspension will yield approximately 10000cpm¹²⁵The I-SP ratio binds (approximately 50000 cells to 200000 cells). In this binding assay, 200. mu.l of cells are added to a test tube containing 20. mu.l of 1.5-2.5nM¹²⁵I-SP and 20. mu.l of unlabelled substance P or any other compound to be tested. The tube was incubated at 4 ℃ or room temperature for 1 hour with slow shaking. Conjugation was performed with GF/C filters (BRANDEL, Gaithersburg, Md.) pre-wetted with 0.1% polyethyleneimineIs separated from unbound radioactivity. Rinsing buffer (50mM Tris pH7.5, 5mM mNCl) with 3ml₂150mM NaCl) was washed 3 times and its radioactivity was measured by a gamma-counter.

Can also be determined by measuring IP₃Accumulation of the degradation product, inositol monophosphate, activation of phospholipase C by NK1R was determined in CHO cells expressing human NK 1R. CHO cells were seeded in 12-well plates at 250000 cells per well. After 4 days in CHO medium, at 0.025. mu. Ci/ml³The cells were loaded with H-inositol and incubated overnight. Extracellular radioactivity was removed by rinsing with phosphate buffered saline. LiCl was added to each well at the final concentration of 0.1mM, with or without the addition of the test sample, and incubation was continued for 15 minutes at 37 ℃. Substance P was added to each well at a final concentration of 0.3nM to activate human NK 1R. After incubation at 37 ℃ for 30 minutes, the medium was removed and 0.1N HCl was added. Each well was sonicated at 4 ℃ and treated with CHCl₃Extracting with methanol (1: 1). The water was loaded against a 1ml dowex ag 1X8 ion exchange column. The column was washed with 0.1N formic acid followed by 0.025M ammonium formate to 0.1N formic acid. Inositol-phosphate was eluted with 0.2M ammonium formate-0.1N formic acid and quantified using a beta counter.

It is also possible to resort to the Lei et al,british pharmaceutical journal105, 261-262(1992) to demonstrate the activity of the compounds of the invention.

The compounds of the present invention are useful for the treatment of a variety of clinical conditions characterized by the presence of excessive tachykinin, in particular substance P, activity.

Thus, for example, over-activation of tachykinins and in particular substance P may be implicated in a number of diseases of the central nervous system. The diseases include affective disorders such as depression or especially depression, for example single episode or recurrent depression and dysthymia or bipolar disorders, for example bipolar I disorder and bipolar II disorder, and cyclothymia; anxiety disorders, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias such as specific animal phobias, social phobias, obsessive-compulsive disorders, stress disorders, including post-traumatic stress disorder and acute stress disorder, and anxiety disorders in general; schizophrenia and other psychotic disorders, such as schizophreniform disorder, schizoaffective disorder, delusional disorder, transient psychotic disorder, shared psychotic disorder (shared psychiatric disorders) and delusional or hallucinogenic psychosis; delirium, dementia, and amnestic and other cognitive neurodegenerative diseases such as Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, vascular dementia and other types of dementia, such as dementia due to HIV disease, head trauma type, Parkinson's disease, Huntington's disease, pick's disease, Creutzfeldt-Jakob disease or dementia due to multiple etiologies; parson's disease and other extravertebral movement disorders such as drug-induced movement disorders, e.g., neuro-parkinsonism induced by neuroleptics, toxic syndrome induced by neuroleptics, acute dystonia induced by neuroleptics, acute sedentary phobia induced by neuroleptics, tardive dyskinesia induced by neuroleptics, and postural tremor induced by drugs; substance-related disorders resulting from the use of alcohol, amphetamine (or amphetamine-like drugs), caffeine, cannabis, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioids, phenylglycine derivatives, sedatives, hypnotics and anxiolytics, including dependence and abuse, intoxication, withdrawal, intoxication delirium, withdrawal delirium, persisting dementia, psychosis, affective disorders, anxiety, sexual dysfunction and insomnia; epilepsy; down syndrome; demyelinating diseases such as MS and ALS and other neuropathological diseases such as peripheral neuropathies, e.g. diabetic and chemotherapy-induced neuropathies, as well as postherpetic, trigeminal, nodal or intercostal and other neuralgia; cerebral vascular diseases such as cerebral vascular sclerosis, subarachnoid hemorrhage or cerebral edema, which are caused by acute and chronic cerebral vascular injuries.

The action of tachykinins and especially substance P is also involved in nociception and pain. The compounds of the invention are therefore useful in the prevention or treatment of diseases and conditions in which pain predominates, including soft tissue and peripheral injuries such as acute trauma, osteoarthritis, rheumatoid arthritis, musculoskeletal pain, especially post-traumatic pain, spinal pain, myofascial pain syndrome, headache, vulvotomy pain, and burns; deep and visceral pain, such as cardiac pain, muscular pain, ocular pain, mouth and face pain, e.g. dental pain, abdominal pain, gynaecological pain, e.g. dysmenorrhoea, labor pain; pain associated with nerve and root damage, such as pain associated with peripheral neuropathies, e.g., nerve entrapment (nerve endipment) pain and peptide plexus extraction pain, amputation pain, peripheral neuralgia, trigeminal neuralgia, atypical facial pain, nerve root damage, and arachnoiditis; pain associated with cancer (commonly referred to as cancer pain); central nervous system pain, such as pain due to spinal cord or brainstem injury; lower back pain; sciatica; ankylosing spondylitis, gout; and scar pain.

Antagonists of tachykinins and especially substance P may also be useful in the treatment of respiratory disorders, particularly disorders associated with excessive mucus secretion such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, bronchospasm; inflammation such as enteritis, psoriasis, fibrosis, osteoarthritis, rheumatoid arthritis, pruritus and sunburn; allergic reactions such as eczema and rhinitis; hypersensitivity disorders such as hypersensitivity to poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, etc.; ophthalmic diseases associated with cell proliferation such as proliferative vitreoretinopathy; dermatological diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.

Antagonists of tachykinins and especially substance P may also be useful in the treatment of tumours, including breast tumours, ganglioblastomas and small cell cancers such as small cell lung cancer.

Antagonists of tachykinins and especially substance P may also be useful in the treatment of Gastrointestinal (GI) disorders including GI tract inflammation such as gastritis, gastroduodenal ulcer, gastric cancer, gastric lymphoma, disorders associated with visceral neuronal control, ulcerative colitis, crohn's disease, irritable bowel syndrome and emesis, including acute, delayed or early emesis such as emesis caused by chemotherapy, radiation, toxins, viral or bacterial infection, pregnancy, vestibular disorders (such as movement disorders, vertigo, dizziness and meniere's disease), surgery, migraine, intracranial pressure changes, gastroesophageal reflux disease, hyperacidity dyspepsia, food or drink hyperkalemia, hyperacidity, heartburn or regurgitation, heartburn (e.g. episodic nocturnal or meal-induced heartburn) and dyspepsia-induced emesis.

Tachykinin and in particular substance P antagonists may also be useful in the treatment of a number of other disorders, including stress-related somatic disorders; reflex sympathetic neurotrophic disorders such as shoulder/hand syndrome; adverse immune responses such as graft tissue rejection, and diseases associated with immune enhancement or suppression such as systemic lupus erythematosus; plasma extravasation resulting from cytokine chemotherapy, diseases of bladder function such as cystitis, detrusor hyperreflexia, and incontinence; fibrosis and collagen diseases such as scleroderma and eosinophilic fascioliasis; blood flow disorders caused by vasodilation and vasospasm such as angina pectoris, vascular headache, migraine and Reynaud's disease; and pain or nociception due to or related to any of the above-mentioned diseases, particularly pain transmission in migraine.

The compounds of the present invention are also effective in treating the combined symptoms of the above-mentioned diseases, especially in treating combined postoperative pain and postoperative nausea and vomiting.

The compounds of the invention are particularly useful in the treatment of emesis, including acute, delayed or early emesis such as chemotherapy, radiation, toxins, pregnancy, vestibular disorders, exercise, surgery, migraine headache, and emesis caused by intracranial pressure fluctuations. More particularly, the compounds of the present invention are useful in the treatment of emesis induced by anti-tumor (cytotoxic) agents, including drugs commonly used in cancer chemotherapy.

Examples of the above-mentioned chemotherapeutic agents include alkylating agents such as nitrogen mustards, aziridines, alkylsulfonates and other compounds having an alkylating action such as nitrosoureas, cisplatin and dacarbazine; antimetabolites such as folic acid, purine or pyrimidine antagonists; nuclear fission inhibitors such as vinca alkaloids podophyllotoxin derivatives; and cytotoxic antibiotics.

Specific examples of chemotherapeutic agents have been described, for example, by d.j. stewart in "Nausea and vomitting: recent Research and Clinical Advances "(eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Florida, USA (1991), p177-203, especially p 188). The chemotherapeutic agents commonly used are cisplatin, Dacarbazine (DTIC), actinomycin. Nitrogen mustards, streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin, daunorubicin, procarbazine, erythromycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, and chlorambucil [ R.J.Gralla et al, cancer treatment Reports, 68(1), 163-flac 172(1984) ].

The compounds of the invention may also be useful in the treatment of emesis induced by radiation (including radiotherapy, such as that used in the treatment of cancer) or radiation sickness; and to treat postoperative nausea and vomiting.

For the treatment of certain diseases, it is desirable to use the compounds of the present invention together with other pharmaceutically effective agents. It is understood that the compounds of the present invention may be used simultaneously, separately or sequentially with another therapeutic agent as a combined preparation to reduce emesis. The combined preparation may be in the form of a two-pack, for example.

In another aspect, the invention provides compounds of the invention and 5-HT₃Antagonists (such as ondansetron, glycopyrrolate, tropisetron or zatisetron) or other anti-emetic drugs (such as dexamethasone) or dopamine antagonists (such as metoclopramide). In addition, the compounds of the present invention may be used in combination with anti-inflammatory corticosteroids (such as dexamethasone). Furthermore, as indicated above, the compounds of the invention may also be combined with chemotherapeutic agents such as alkylating agentsAn antimetabolite, an inhibitor of nuclear division or a cytotoxic antibiotic. Generally, an effective dosage form common to known therapeutic agents is suitable for use in such combination.

When an experiment was conducted using a ferret model (f.d. tattersall et al, eur.j. pharmacol., (1993)250, R5-R6) for a snowmouse model of cisplatin-induced emesis, it was found that the compounds of the present invention can attenuate retching and vomiting induced by cisplatin.

The compounds of the invention are also useful, inter alia, in the treatment of pain or nociception and/or inflammation and conditions associated therewith such as neuropathies, for example diabetic and chemotherapy-induced neuropathies, post-herpetic and other neuralgia, asthma, osteoarthritis, rheumatoid arthritis and headaches (including migraine headaches), acute or chronic pressure headaches, cluster headaches, temporomandibular pain, and mandibular sinus pain. The invention also provides methods of using the compounds of the invention in therapy.

In another aspect, the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a physiological disorder associated with an excess of tachykinins, particularly substance P.

The invention also provides a method of treating or preventing a physiological disorder associated with an excess of tachykinins, particularly substance P, comprising administering to a patient in need thereof a tachykinin reducing amount of a compound of the invention or a composition comprising a compound of the invention.

For the treatment of certain diseases, it is desirable to use the compounds of the present invention together with other pharmaceutically effective agents. For example, for the treatment of respiratory disorders such as asthma, the compounds of the present invention may be combined with bronchodilators such as beta₂-an adrenergic receptor antagonist or a tachykinin antagonist acting on the NK-2 receptor. The compound of the invention and the bronchodilator are administered to the patient simultaneously, sequentially or in combination. For the treatment of conditions which require antagonism of neurokinin-1 and neurokinin-2 including conditions associated with bronchoconstriction and/or plasma extravasation in the airways such as asthma, chronic bronchitis,Airway disorders, or bladder fibrosis, compounds of the invention may be used with tachykinin antagonists acting at the neurokinin-2 receptor or tachykinin receptor antagonists acting at the neurokinin-1 and neurokinin-2 receptors.

Likewise, the compounds of the present invention may be used in combination with leukotriene antagonists such as leukotriene D₄Antagonists (e.g. compounds selected from european patent specifications 0480717 and 0604114, US patents 4,859,692 and 5,270,324) are used together. The combined application is especially useful for treating respiratory diseases such as asthma, chronic bronchitis and cough.

Accordingly, the present invention provides a method of treating a respiratory disorder, such as asthma, which comprises administering to a patient in need thereof an effective amount of a compound of the present invention and an effective amount of a bronchodilator. The invention also provides a composition comprising a compound of the invention, a bronchodilator and a pharmaceutically acceptable carrier.

It is understood that for the treatment or prevention of migraine, the compounds of the present invention may be combined with other anti-migraine agents such as ergotamines or 5-HT₁Agonists, especially sumatriptan or rizatriptan, are used together. Similarly, for the treatment of behavioral hyperalgesia, the compounds of the present invention may be used in combination with an N-methyl D-aspartate (NMDA) antagonist such as dizocilpine. For the treatment or prevention of lower urinary tract inflammation, particularly cystitis, the compounds of the present invention may be used in combination with an anti-inflammatory agent such as a bradykinin receptor antagonist. The invention also provides compositions comprising a compound of the invention, a bronchodilator and a pharmaceutically acceptable carrier.

It will be appreciated that for the treatment or prophylaxis of pain or nociception, the compounds of the invention may be used in conjunction with other analgesics such as paracetamol (paracetamol), aspirin or other NSAIDs, especially opioid analgesics (especially morphine). Specific anti-inflammatory agents include diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam and sulindac. Suitable opioid analgesics for use with the compounds of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, afentanil, buprenorphine, butonopine, fentanyl, sufentanil, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof. Preferred salts of these opioid analgesics include morphine sulfate, morphine hydrochloride, morphine tartrate, codeine phosphate, codeine sulfate, dihydrocodeine ditartrate, diacetylmorphine hydrochloride, hydrocodone ditartrate, hydromorphone hydrochloride, levorphanol tartrate, oxymorphone hydrochloride, afentail hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, fentanyl citrate, meperidine hydrochloride, methadone hydrochloride, nalbuphine hydrochloride, dextromethorphan naphthalenesulfonic acid (2-naphthalenesulfonic acid (1: 1) -hydrate), and pentazocine hydrochloride.

Thus, in a further aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention and an analgesic agent, together with at least one pharmaceutically acceptable carrier or excipient.

In a further aspect, the invention provides a product containing a compound of the invention and an analgesic as a combined preparation which can be applied simultaneously, separately or sequentially in the treatment and prevention of pain or nociception.

It is understood that the compounds of the present invention may be used in combination with an antidepressant or anxiolytic agent for the treatment or prevention of depression and/or anxiety. Suitable antidepressants for use in the present invention include noradrenaline reuptake inhibitors and selective 5-hydroxytryptamine, which include noradrenaline reuptake inhibitors, selective 5-hydroxytryptamine reuptake inhibitors, monoamine oxidase inhibitors, reversible monoamine oxidase inhibitors, 5-hydroxytryptamine and noradrenaline reuptake inhibitors, Corticotropin Releasing Factor (CRF) antagonists, alpha-adrenoceptor antagonists and atypical antidepressants. Another class of antidepressants useful in the present invention are noradrenergic and specific 5-hydroxytryptamine-potent antidepressants such as mirtazapine. Suitable examples of noradrenaline reuptake inhibitors include amitriptyline, clomipramine, doxepin, mipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, reboxetine, and protriptyline, and pharmaceutically acceptable salts thereof. Examples of suitable selective 5-hydroxytryptamine reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine, and sertraline, and pharmaceutically acceptable salts thereof. Examples of suitable monoamine oxidase inhibitors include isocarboxazid, phenelzine, tranylcypromine and selegiline and their pharmaceutically acceptable salts. Examples of suitable reversible monoamine oxidase inhibitors include moclobemide and its pharmaceutically acceptable salts. Examples of suitable 5-hydroxytryptamine and norepinephrine reuptake inhibitors include venlafaxine and pharmaceutically acceptable salts thereof. Examples of suitable Corticotropin Releasing Factor (CRF) antagonists include the compounds described in International patent Specifications WO94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677. Examples of suitable atypical antidepressants include bupropion, lithium, nefazodone, sibutramine, trazodone and viloxazine and their pharmaceutically acceptable salts. Other antidepressants useful in the invention include adinozolam, alapropyl, amineptine, apigenin/chloranil * combination, atipamezole, azamianserin, parnapine, fefuraline, diphenylmelphalan, binodaline, biprazineol, bromofamine, bupropion, caroxazone, cericlamine, cyanamide, simoxanone, citalopram, clomeprol, clovoxamine, chloro * denier, deanol, demetirelin, diphenylazepine, dutepin, droxidopa, diethyloxin, setazolam, etoperidone, femoxetine, phenagabine, fexolamine, flutricine, idazoxan, indamine, indoloclorine, iprindoline, levoprotiline, litoxetine, lofepramine, medroxamin, memaxamine, milnacipramine, tryptiline, tiazepine, fenadine, tiazepine, mefenadine, sercloremine, sertraline, sibutramine, sulbuthionine, sulpiride, tenixazone, toprazinone, thymoliberin, tianeptine, teflecainide, toffenacin, tofisopam, toloxatone, tomoxetine, vilapride, viloquinoline, zimelidine and zometapine and their pharmaceutically suitable salts, and the st.john's herbal plant (hypericum perforatum) or extracts thereof. Preferred antidepressants include selective 5-hydroxytryptamine reuptake inhibitors, especially fluoxetine, fluvoxamine, paroxetine and sertraline and pharmaceutically acceptable salts thereof.

Suitable anxiolytics for use in the present invention include benzodiazepines * and 5-HT_1AAgonists or antagonists (especially 5-HT)_1APartial agonists) and Corticotropin Releasing Factor (CRF) antagonists. In addition to benzodiazepines *, other suitable anxiolytics are non-benzodiazepines * class sedative-sleeping drugs such as zolpidem; mood stabilizers such as clobazam, gabapentin, lamotrigine, loreclezole, oxcarbazepine, stitepol and vigabatrin; and barbiturates. Suitable benzodiazepines * for use in the present invention include alprazolam, chlordiazepoxide *, clonazepam, chlorazepate, diazepam, halazepam, lorezepam, oxazepam and pramipepam and pharmaceutically acceptable salts thereof. Suitable 5-HT for use in the present invention_1AAgonists or antagonists, especially 5-HT_1APartial agonists include buspirone, fluxolone, gepirone, ixabepilone and lnpirole and pharmaceutically acceptable salts thereof. Suitable Corticotropin Releasing Factor (CRF) antagonists include the compounds described in International patent Specifications WO94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677. Another class of anxiolytic agents for use in the present invention are compounds having muscarinic cholinergic activity. Suitable compounds in this class include ml muscarinic cholinergic receptor antagonists such as those described in european patent specifications 0709093, 0709094 and 0773021 and international patent specification WO 96/12711. Another class of anxiolytics for use in the present invention are compounds that act on ion channels. Such suitable compounds include carbamazepine, lamotrigine and valproate and their pharmaceutically acceptable salts.

Thus, in a further aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention and an antidepressant or anxiolytic agent in combination with at least one pharmaceutically acceptable carrier or excipient.

Suitable antipsychotics for use in combination with a compound of the present invention include phenothiazine, thianthrene, heterocyclic benzophenones *, propylphenones, diphenylbutylpiperidine and indolone classes of antipsychotic. Examples of suitable phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Examples of suitable thioanthracenes include chlorprothixene and thiothixene. Examples of suitable classes of diphenyl nitrogens * include clozapine and olanzapine. An example of a propylphenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindone. Other antipsychotic agents include loxapine, sulpiride and risperidone. It is understood that the antipsychotic agent when used in combination with a compound of the present invention may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride (heptanoate, decanoate), trifluoperazine hydrochloride, thiothixene hydrochloride, flupiperidinase decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, olanzapine, haloperidol, pimozide and risperidone are generally used in non-salt forms.

Other antipsychotic agents useful in combination with the compounds of the present invention include dopamine receptor antagonists, especially D₂、D₃And D₄Dopamine receptor antagonists, and muscarinic ml receptor agonists, D₃An example of a dopamine receptor antagonist is the compound PNU-99194A. D₄An example of a dopamine receptor antagonist is PNU-101387. An example of a muscarinic ml receptor agonist is xanomeline.

Another class of antipsychotics for use in combination with a compound of the present invention is 5-HT_2AReceptor antagonists, examples of which include MDL 100907 and fananserin. For use with the compounds of the inventionAlso useful are 5-hydroxytryptamine dopamine antagonists (SDAs), which are believed to combine 5-HT_2AAnd dopamine receptor antagonist activity, examples of which are olanzapine and ziprasidone.

Thus, in a further aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention and an antipsychotic agent, together with at least one pharmaceutically acceptable carrier or excipient.

The compounds of the present invention and other pharmaceutically effective agents may be administered to the patient simultaneously, sequentially or in combination. It is understood that when the agents of the present invention are used in combination, the compound of the present invention and the other pharmaceutically effective agent may be administered in the same pharmaceutically acceptable carrier and simultaneously. They may also be administered in separate pharmaceutical carriers (e.g., conventional oral dosage forms) and concurrently. The term "concurrently" also refers to the case where separate dosage forms are provided and administered sequentially.

Pharmacological studies with the compounds of the present invention provide the possibility of applying them at low doses, so that the risk of unwanted side effects can be minimized.

The compounds of the invention are administered to subjects (animals and humans) in need of such treatment in dosages that provide the best pharmaceutical effect. It is understood that the dosage required for any particular use will vary with the patient, not only with the particular compound or composition selected but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, the drug or special diet used in conjunction with the patient, and other factors known to those skilled in the art, the appropriate dosage required ultimately being at the discretion of the attendant physician.

In the treatment of conditions associated with an excess of tachykinins, suitable doses will generally be in the range of about 0.001 to 50mg/kg body weight/day, in single or multiple doses. A preferred dosage is about 0.01 to 25mg/kg body weight/day, more preferably about 0.05 to 10mg/kg body weight/day. For example, in the treatment of neurotransmitter disorders associated with painful sensations, suitable dosages are about 0.001 to 25mg/kg body weight/day, preferably 0.005 to 10mg/kg body weight/day, especially about 0.01 to 5mg/kg body weight/day. The compound may be administered 1-4 times per day, preferably 1 or 2 times per day. In the treatment of emesis, a suitable dose is about 0.001-10 mg/kg body weight/day, preferably 0.005-5 mg/kg body weight/day, especially about 0.01-1 mg/kg body weight/day. The compound may be administered 1-4 times per day, preferably 1 or 2 times per day. In the treatment or prevention of diseases of the central nervous system, suitable dosages are about 0.001 to 10mg/kg body weight/day, preferably about 0.005 to 5mg/kg body weight/day, especially about 0.01 to 1mg/kg body weight/day. The compound may be administered 1-4 times per day, preferably 1 or 2 times per day.

It is understood that the dosage of the compounds of the invention required for any treatment will vary not only with the particular compound selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient and will ultimately be at the discretion of the attendant physician.

The pharmaceutical compositions of the invention may be employed in the form of pharmaceutical formulations (e.g. in solid, semi-solid or liquid) containing one or more compounds of the invention as active ingredients together with organic or inorganic carriers or excipients suitable for topical, enteral or parenteral administration. The active ingredient may be mixed with, for example, pharmaceutically conventional non-toxic carriers, and formulated into tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable dosage form. Carriers which may be used are water, glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silicic acid, potato starch, urea and other carriers suitable for the preparation of solid, semi-solid and liquid dosage forms, and in addition adjuvants, stabilizers, thickeners, colorants and flavors. The effective amount of the compound contained in the pharmaceutical composition should be sufficient to produce the desired effect on the protrusion or condition of the disease.

For the preparation of solid dosage forms, e.g., tablets, the active ingredient is mixed with a pharmaceutically acceptable carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutically acceptable diluents, e.g., water, to provide a solid preformulation composition containing a homogeneous mixture of a compound of the present invention or a pharmaceutically acceptable non-toxic salt thereof. When referring to the preformulation composition as homogeneous, it is meant that the active ingredient is distributed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pellets and capsules. The solid preformulation composition may be subdivided into unit dosage forms as described above containing from about 0.1 to 500mg of the active ingredient of the present invention. Tablets or pellets of the novel composition may be coated or otherwise compounded to provide a dosage form exhibiting prolonged action. For example, a tablet or pellet may constitute an inner or outer dosage element, with the outer dosage element being wrapped over the inner dosage element. The two layers may be separated by an enteric layer that resists disintegration in the stomach and allows the inner layer components to pass intact into the duodenum for delayed release. A variety of materials may be used as the enteric layer or coating, including various polymeric acids and mixtures of polymeric acids as well as shellac, cetyl alcohol and cellulose acetate.

Liquid forms of the novel compositions of the present invention for oral or parenteral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, emulsions (prepared with suitable oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, or solubilizing or emulsifying agents suitable for intravenous use), elixirs and similar pharmaceutical dosage forms. Aqueous suspensions suitable dispersing or suspending agents include synthetic or natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

The composition for oral inhalation or nasal inhalation includes a solution or suspension and a powder in pharmaceutically acceptable water or an organic solvent or a mixture thereof. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. The composition is preferably administered by the oral or nasal respiratory route to produce a local or systemic effect. The composition in a sterile pharmaceutically acceptable solvent may be sparged with an inert gas. The insufflation solution may be inhaled directly from the insufflation device, or the insufflation device may be connected to a face mask, tent or pulsed positive pressure ventilator. The inhalation solution, suspension or powder composition is administered orally or nasally in a suitable manner from the device delivering the composition.

For the treatment of the clinical conditions and diseases mentioned above, the compounds of the invention may be administered orally, topically, parenterally, by inhalation spray or rectally in unit dosage forms containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrathoracic injection or infusion.

The following examples detail the process for preparing the crystalline forms of the invention. The following examples are given for the purpose of illustrating the invention and should not be construed as limiting the scope or spirit of the invention.

Example 1(S) - (4-fluorophenyl) glycine Manual synthesis: step A: 3- (4-fluorophenyl) acetyl-4- (S) -benzyl-2-oxazolidinone

A dry 1L three-necked flask, equipped with a connector, nitrogen inlet, thermometer and magnetic stir bar, was purged with nitrogen and charged with a solution of 5.09g (33.0mmol) of 4-fluorophenylacetic acid in 100ml of dry diethyl ether. The solution was cooled to-10 ℃ and treated with 5.60ml (40.0mmol) triethylamine followed by 4.30ml (35.0mmol) trimethylacetyl chloride. A white precipitate formed immediately. The resulting mixture was stirred at 10 ℃ for 40 minutes and then cooled to-78 ℃.

A dried 250ml round bottom flask fitted with a linker and magnetic stir bar was purged with nitrogen and 5.31g (30.0mmol) of 4- (S) -benzyl-2-oxazolidinone in 40ml anhydrous THF was added. The solution was stirred in a dry ice/acetone bath for 10 minutes, then 18.8ml of a 1.6M solution of n-butyllithium in hexane were added slowly. After 10 minutes, the lithiated oxazolidinone solution was added via cannula to a three-necked flaskIn the mixture. The resulting mixture was removed from the cooling bath and the temperature was raised to 0 ℃. The reaction was quenched by addition of 100ml of saturated aqueous ammonium chloride solution, transferred to a 1L flask, and the ether and THF were removed in vacuo. The concentrated mixture was partitioned between 300ml dichloromethane and 50ml water and the two layers were separated. The organic layer was washed with 200ml of 2N dilute hydrochloric acid, 300ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 400g silica gel with 3: 2 v/v hexane/ether as eluent gave 8.95g of an oil which slowly solidified on standing. Recrystallization from 10: 1 hexane/diethyl ether gave 7.89g (83%) of the title compound as a white solid, mp 64-66 ℃. Mass spectrum (FAB): M/Z314 (M + H, 100%), 177 (M-ArCH)₂CO+H，85％).¹H-NMR(400MHz，CDCl₃): δ 2.76(dd, 1H, J ═ 13.2, 9.2), 3.26(dd, J ═ 13.2, 3.2), 4.16-4.34(m, 4H), 4.65-4.70(m, 1H), 7.02-7.33(m, 9H), elemental analysis: calculated value, C₁₈H₁₆FNO₃: c, 69.00; h, 5.15; n, 4.47; f, 6.06; measurement value: c, 68.86; h, 5.14; n, 4.48; f, 6.08.And B: 3- ((S) -azido- (4-fluorophenyl)) acetyl-4- (S) -benzyl 2-oxazolidinones

A dry 1L three-necked flask equipped with a connector, nitrogen inlet, thermometer and magnetic stir bar was purged with nitrogen and 58.0ml of a 1M solution of potassium bis (trimethylsilyl) amide in toluene and 85ml of THF were added and cooled to-78 ℃. A dried 250ml round bottom flask fitted with a linker and magnetic stir bar was flushed with nitrogen and a solution of 7.20g (23.0mmol)3- (4-fluorophenyl) acetyl-4- (S) -benzyl-2-oxazolidinone in 40ml THF was added. The acyl oxazolidinone solution was stirred in a dry ice/acetone bath for 10 minutes and then transferred via cannula into the potassium bis (trimethylsilyl) amide solution at a rate that maintained the internal temperature of the mixture below-70 ℃. The acyl oxazolidinone flask was rinsed with 15ml of THF, the rinse was added to the reaction mixture via cannula, and the resulting mixture was stirred at-78 deg.C for 30 minutes. A dried 250ml round bottom flask fitted with a coupling and magnetic stir bar was flushed with nitrogen and 40ml of 10.89g (35.0mmol)2, 4, 6-triisopropylphenylsulfonylazideTHF solution. The azide solution was stirred in a dry ice/acetone bath for 10 minutes and then transferred via cannula into the reaction mixture at a rate that maintained the internal temperature of the mixture below-70 ℃. After 2 minutes, 6.0ml of glacial acetic acid were added to quench the reaction, the cooling bath was removed and the mixture was stirred at room temperature for 18 hours. The quenched reaction mixture was partitioned between 300ml ethyl acetate and 300ml 50% saturated aqueous sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 500g silica gel with 2: 1v/v then 1: 1v/v hexane/dichloromethane as eluent gave 5.45g (67%) of the title compound as an oil. Infrared Spectrum (neat, cm)^-1)：2104，1781，1702¹H-NMR(400MHz，CDCl₃): δ 2.86(dd, 1H, J ═ 13.2, 9.6), 3.40(dd, 1H, J ═ 13.2, 3.2), 4.09-4.19(m, 2H), 4.62-4.68(m, 1H), 6.14(s, 1H), 7.07-7.47(m, 9H) elemental analysis: calculated value, C₁₈H₁₅FN₄O₃: c, 61.01; h, 4.27; n, 15.81; f, 5.36; measurement value: c, 60.99; h, 4.19; n, 15.80; f, 5.34.And C: (S) -azido- (4-fluorophenyl) acetic acid

5.40g (15.2mmol) of 3- ((S) -azido- (4-fluorophenyl) acetyl-4- (S) -benzyl-2-oxazolidinone in 200ml of a 3: 1v/v THF/water solution are stirred in an ice bath for 10 minutes 1.28g (30.4mmol) of lithium hydroxide monohydrate are added in one portion and the resulting mixture is stirred under cooling for 30 minutes the reaction mixture is partitioned between 100ml of dichloromethane and 100ml of 25% saturated aqueous sodium bicarbonate solution and the two layers are separated, the aqueous layer is washed with 2X 100ml of dichloromethane and acidified to pH2 with 2N dilute hydrochloric acid, the resulting mixture is extracted with 2X 100ml of ethyl acetate, the extracts are combined, washed with 50ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 2.30g (77%) of the title compound, as an oil, which was used in the next step without further purification. Infrared Spectrum (neat, cm)^-1)：2111，1724。¹H-NMR(400MHz，CDCl₃)：δ5.06(s，1H)，7.08-7.45(m，4H)，8.75(br s，1H)。Step D: (S) - (4-fluorophenyl) glycine

A mixture of 2.30g (11.8mmol) of (S) -azido- (4-fluorophenyl) acetic acid, 250mg of 10% palladium-on-carbon catalyst and 160ml of 3: 1v/v water/acetic acid was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through celite and the flask and filter cake were washed thoroughly with about 1L of 3: 1v/v water/acetic acid. The filtrate was concentrated in vacuo to a volume of about 50 ml. 300ml of toluene were added and the mixture was concentrated to give a solid. The solid was suspended in 1: 1v/v methanol/ether, filtered and dried to give 1.99g (100%) of the title compound.¹H-NMR(400MHz，D₂O+NaOD)：δ3.97(s，1H)，6.77(app t，2H，J＝8.8)，7.01(appt，2H，J＝5.6).Splitting: step A': 4-fluorophenyl acetyl chloride

A solution of 150g (0.974mol) of 4-fluorophenylacetic acid and 1ml of N, N-dimethylformamide in 500ml of toluene at 40 ℃ is treated with 20ml of thionyl chloride and heated to 40 ℃. An additional 61.2ml of thionyl chloride was added dropwise over 1.5 hours. After the addition was complete the solution was heated at 50 ℃ for 1h, the solvent was removed in vacuo and the residual oil was distilled under reduced pressure (1.5mmHg) to give 150.4g (89.5%) of the title compound, bp 68-70 ℃.Step B': 2-bromo-2- (4-fluoro) phenylacetic acid methyl ester

A mixture of 150.4g (0.872mol) of 4-fluorophenylacetyl chloride and 174.5g (1.09mol) of bromine was irradiated with a quartz lamp at 40 to 50 ℃ for 5 hours. The reaction mixture was added dropwise to 400ml of methanol, and the solution was stirred for 16 hours. The solvent was removed in vacuo and the residual oil was distilled under reduced pressure (1.5mmHg) to give 198.5g (92%) of the title compound, bp 106-.Step C': methyl (+/-) - (4-fluorophenyl) glycine

A solution of 24.7g (0.1mol) of methyl 2-bromo-2- (4-fluoro) phenylacetate and 2.28g (0.01mol) of benzyltriethylammonium chloride in 25ml of methanol was treated with 6.8g (0.105mol) of sodium azide, and the resulting mixture was stirred at room temperature for 20 hours. Filtering the reaction mixture; the filtrate was diluted with 50ml of methanol and hydrogenated in the presence of 0.5g of 10% Pd/C at 50psi for 1 hour. The solution was filtered and the solvent removed in vacuo. The residue was partitioned between 10% aqueous sodium carbonate and ethyl acetate. The organic phase was washed with water, saturated aqueous sodium chloride solution and magnesium sulfateDried and concentrated in vacuo to give 9.8g of the title compound as an oil.Step D': (S) - (4-fluorophenyl) glycine methyl ester

58.4g (. + -.) -4-fluoromethylglycine methyl ester in 110ml of a 7: 1v/v ethanol/water solution were mixed with 28.6g (0.0799mol) of O, O' - (+) -dibenzoyltartaric acid ((+) -DBT) (28.6g, 0.0799mol) in 110ml of a 7: 1 ethanol/water solution, and the resulting solution was aged at room temperature. After completion of crystallization, ethyl acetate (220ml) was added, and the resulting mixture was cooled to-20 ℃ and filtered to obtain 32.4g of(s) - (4-fluorophenyl) glycine methyl ester, (+) -DBT salt (ee ═ 93.2%). The mother liquor was concentrated in vacuo and the free base was liberated by partitioning between ethyl acetate and aqueous sodium carbonate. 110ml of a 7: 1v/v ethanol/water solution of the free base obtained were mixed with 28.6g (0.0799mol) of O, O' - (-) -dibenzoyltartaric acid ((-) -DBT) (28.6g, 0.0799mol) of 110ml of a 7: 1v/v ethanol/water solution, and the resulting solution was kept at room temperature. After completion of crystallization, ethyl acetate (220ml) was added, and the resulting mixture was cooled to-20 ℃ and filtered to obtain 47.0g of (r) - (4-fluorophenyl) glycine methyl ester, (-) -DBT salt (ee 75.8%). The mother liquor was reused and (+) -DBT was added to give a second batch of 7.4g of(s) - (4-fluorophenyl) glycine ester, (+) -DBT salt (ee ═ 96.4%). Two batches of (S) -amino ester (39.8g) were mixed in 200ml of 7: 1v/v ethanol/water, heated for 30 minutes and cooled to room temperature. Ethyl acetate was added, cooled and filtered to give 31.7g of (S) - (4-fluorophenyl) glycine ester, (+) -DBT salt (ee > 98%). The percent enantiomeric excess (ee%) (Crownpakc (+) 5% MeOH in HClO) was determined by manual HPLC₄Aqueous solution, pH2, 1.5 ml/min, 40 ℃, 200 nm). A mixture of 17.5g of (S) - (4-fluorophenyl) glycine ester, (+) -DBT salt and 32ml of 5.5N HCl (32ml) was heated under reflux for 1.5 hours. The reaction mixture is concentrated in vacuo and the residue is dissolved in 40ml of water. The aqueous solution was washed with 3X 30ml of ethyl acetate and the two layers were separated. The pH of the aqueous layer was adjusted to 7 with ammonium hydroxide, and the precipitated solid was filtered to obtain 7.4g of the title compound (ee ═ 98.8%).

Example 23- (S) - (4-fluorophenyl) -4-benzyl-2-morpholinone Step A: n-benzyl (S) - (4-fluorophenyl) glycinAcid(s)

A solution of 1.87g (11.05mmol) of (S) - (4-fluorophenyl) glycine and 1.12ml (11.1mmol) of benzaldehyde in 11.1ml of 1N aqueous sodium hydroxide solution and 11ml of methanol is treated with 165mg (4.4mmol) of sodium borohydride at 0 ℃. The cooling bath was removed and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added a second portion of benzaldehyde (1.12ml (11.1mmol)) and 165mg (4.4mmol) of sodium borohydride, and stirring was continued for 1.5 hours. The reaction mixture was partitioned between 100ml of diethyl ether and 50ml of water and the two layers were separated. The aqueous layer was separated and filtered to remove a small amount of insoluble material. The filtrate was acidified to pH5 with 2N dilute hydrochloric acid, and the precipitated solid was filtered off, washed thoroughly with water and then ether to give 1.95g of the title compound.¹H-NMR(400MHz，D₂O+NaOD)：δ3.33(AB q，2H，J＝8.4)，3.85(s，1H)，6.79-7.16(m，4H).And B: 3- (S) - (4-fluorophenyl) -4-benzyl-2-morpholinone

A mixture of 1.95g (7.5mmol) of N-benzyl (S) - (4-fluorophenyl) glycine, 3.90ml (22.5mmol) of N, N-diisopropylethylamine, 6.50ml (75.0mmol) of 1, 2-dibromoethane and 40ml of N, N-dimethylformamide is stirred at 100 ℃ for 20 hours (all solids are dissolved while warming). The reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between 250ml of diethyl ether and 100ml of 0.5N potassium hydrogen sulfate solution and the two layers were separated. The organic layer was washed with 100ml of saturated aqueous sodium bicarbonate solution, 3X 150ml of water, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 125g silica gel with 3: 1v/v hexane/ether as eluent gave 1.58g (74%) of the title compound as an oil.¹H-NMR(400MHz，CDCl₃)：δ2.65(dt，1H，J＝3.2，12.8)，3.00(dt，1H，J＝12.8，2.8)，3.16(d，1H，J＝13.6)，3.76(d，1H，J＝13.6)，4.24(s，1H)，4.37(dt，1H，J＝13.2，3.2)，4.54(dt，1H，J＝2.8，13.2)，7.07-7.56(m，9H).

Example 32- (R) - (3, 5-bis (trifluoromethyl) benzoyloxy) -3- (S) - (4) -fluoro) phenyl-4-benzylmorpholine

2.67g (10.0mmol) of 3- (R) - (4-fluoro) A solution of-phenyl-4-benzyl-2-morpholinone in 40ml of anhydrous THF was cooled to-78 ℃. The cold solution was diluted with 12.5ml of 1.0M L-Selectride^*Is treated with a THF solution while maintaining the internal reaction temperature below-70 ℃. The resulting solution was cooled and stirred for 45 minutes, and 3.60ml (20.0mmol) of 3, 5-bis (trifluoromethyl) benzoyl chloride was added to the reaction solution. The resulting cold yellow mixture was stirred for 30 minutes and quenched by the addition of 50ml of saturated aqueous sodium bicarbonate. The quenched mixture was partitioned between 300ml of diethyl ether and 50ml of water and the two layers were separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 300ml of diethyl ether; the extract was dried and combined with the original organic layer. The combined organic layers were concentrated in vacuo. Flash chromatography on 150g silica gel with 37: 3 v/v hexane/ether as eluent gave the title compound as a solid (83% yield).

Mass spectrum (FAB): M/Z528 (M + H, 25%), 270 (100%).¹H NMR(CDCl₃，400MHz，ppm)：δ2.50(dt，J＝3.2，12.0，1H)，2.96(app d，J＝12.0，1H)，2.98(d，J＝13.6，1H)，3.74-3.78(m，1H)，3.81(d，J＝2.8，1H)，3.94(d，J＝13.6，1H)，4.19(dt，J＝ 2.0，12.0)，6.20(d，J＝2.8，1H)，6.99(t，J＝8.4，2H)，7.27-7.38(m，5H)，7.52-7.56(m，2H)，8.09(s，1H)，8.46(s，2H).

Example 4Titanocene dimethyl

A solution of 2.49g (10.0mmol) of titanocene dichloride in 50ml of diethyl ether at 0 ℃ in the dark is treated with 17.5ml of a 1.4M solution of methyllithium in diethyl ether while maintaining the internal temperature below 5 ℃. The resulting yellow/orange mixture was stirred at room temperature for 30 minutes and quenched by the slow addition of 25g of ice. The reaction-terminated mixture was diluted with 50ml of diethyl ether and 25ml of water, and the two layers were separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 2.03g (98%) of the title compound as a light-sensitive solid. The dimethyltitanocene can be stored in toluene solution at 0 ℃ for at least 2 weeks without chemical degradation.¹H NMR(CDCl₃，200MHz，ppm)：δ-0.15(s，6H)，6.06(s，10H)。

Example 52- (R) - (1- (3, 5-bis (trifluoromethyl) phenyl) ethenyloxy) -3- (S) - (4-fluoro) phenyl-4-benzylmorpholine

4.9mmol of 2- (R) - (3, 5-bis (trifluoromethyl) benzoyloxy) -3- (S) - (4-fluoro) phenyl-4-benzylmorpholine and 2.50g (12.0mmol) of dimethyltitanocene in 35ml of a 1: 1v/v THF/toluene solution are stirred in an oil bath at 80 ℃ for 16 h. The reaction mixture was cooled and concentrated in vacuo. Flash chromatography on 150g silica gel with 3: 1v/v hexane/dichloromethane as eluent gave the title compound as a solid (60% yield).

Mass spectrum (FAB): M/Z526 (M + H, 75%), 270 (100%).¹H NMR(CDCl₃，400MHz，ppm)：δ2.42(dt，J＝3.6，12.0)，2.90(app d，J＝12.0，1H)，2.91(d，J＝13.6，1H)，3.62-3.66(m，1H)，3.72(d，J＝2.6)，3.94(d，J＝13.6，1H)，4.09(dt，J＝2.4，12.0，1H)，4.75(d，J＝3.2，1H)，4.82(d，J＝3.2，1H)，5.32(d，J＝2.6，1H)，7.09(t，J＝8.8，2H)，7.24-7.33(m，5H)，7.58-7.62(m，2H)，7.80(s，1H)，7.90(s，2H).

Example 62- (R) - (1- (S) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenylmorpholine and 2- (S) - (1- (R) - (3, 5) -bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenylmorpholine

A mixture of 1.83g (3.5mmol) 2- (R) - (1- (3, 5-bis (trifluoromethyl) phenyl) vinyloxy) -3- (S) - (4-fluoro) phenyl-4-benzylmorpholine and 800mg 5% rhodium-alumina catalyst in 40ml anhydrous ethanol was stirred under a hydrogen atmosphere for 24 h. Filtering the catalyst through a diatomite pad; the reaction flask and filter cake were washed with 200ml ethyl acetate. The filtrate was concentrated in vacuo and the residue was pumped down under high vacuum (1mmHg, room temperature).

The residue was redissolved in 40ml of isopropanol; 800mg of 10% palladium-on-carbon catalyst was added, and the resulting mixture was stirred under a hydrogen atmosphere for 24 hours. The catalyst was filtered through a pad of celite(ii) a The reaction flask and filter cake were washed with 200ml ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography on 50g silica gel with 2: 1v/v hexane/ether and then 3: 2 v/v ether/hexane as eluent gave 283mg of 2- (R) - (1- (S) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenylmorpholine and 763mg of 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenylmorpholine, both as an oil (68% overall yield). For 2- (R) - (1- (S) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenylmorpholine: mass Spectrometry (FAB) M/Z438 (M + H, 65%), 180 (100%).¹H NMR(CDCl₃400MHz, ppm): δ 1.47(d, J ═ 6.8, 3H), 1.87(br s, 1H)), 3.03(dd, J ═ 2.8, 12.8), 3.17(dt, J ═ 4.0, 12.4, 1H), 3.43-3.47(m, 1H), 3.80(dt, J ═ 3.2, 11.6), 4.10(d, J ═ 2.2, 1H), 4.70(q, J ═ 6.8, 1H), 4.87(d, J ═ 2.2, 1H), 6.99-7.03(m, 2H), 7.23-7.27(m, 2H), 7.63(s, 2H), 7.66(s, 1H). For 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenylmorpholine:

mass Spectrometry (FAB) M/Z438 (M + H, 75%), 180 (100%).¹H NMR(CDCl₃，400MHz，ppm)：δ1.16(d，J＝6.8)，1.80(br s，1H)，3.13(dd，J＝3.2，12.4)，3.23(dt，J＝3.6，12.4)，3.63(dd，J＝2.4，11.2)，4.01(d，J＝2.4，1H)，4.13(dt，J＝3.2，12.0)，4.42(d，J＝2.4，1H)，4.19(q，J＝6.8，1H)，7.04-7.09(m，2H)，7.27-7.40(m，4H)，7.73(s，1H).

Example 72- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1, 2, 4-tris) Azole) methylmorpholine Step A: n-methylcarboxyl-2-chloroacetamidinohydrazone (chloroacetamidrazone)

5.0g (66.2mmol) of chloroacetonitrile in 35ml of dry methanol are cooled to 0 ℃ and treated with 0.105g (1.9mmol) of sodium methoxide. The ice bath was removed and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 0.110ml (1.9mmol) of acetic acid, and 5.8g (64.9mmol) of methyl hydrazinecarboxylate. In roomAfter stirring at room temperature for 30 minutes, the suspension was concentrated in vacuo and placed under high vacuum overnight to give 10.5g (98%) of a yellow powder, which was used in part in step C below.And B: 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) Ethoxy) -3- (S) - (4-fluoro) phenyl-4- (2- (N-methylcarboxy) -acetamidohydrazone) morpholine

945mg (2.3mmol) (2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenylmorpholine, 447mg (2.7mmol) N-methylcarboxyl-2-chloro-acetamidohydrazone, and 0.78ml (4.5mmol) N, N-diisopropylethylamine in 17ml acetonitrile are stirred at room temperature for 20 h the reaction solution is concentrated in vacuo and the residue is partitioned between 50ml dichloromethane and 25ml water the organic layer is separated, dried over magnesium sulfate and concentrated in vacuo flash chromatography on 50g silica gel using 50: 1: 0.1 dinitrogen methane/methanol/ammonium oxychloride as eluent to give 1.12g (90%) of the title compound as a foam.And C: 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) Ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1, 2, 4) -triazole) methylmorpholine

1.01g (1.8mmol) of 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (2- (N-methylcarboxylacetamidylhydrazone) morpholine in 15ml xylene was heated at reflux for 2H the reaction was cooled and concentrated in vacuo flash chromatography on 50g silica gel with 50: 1: 0.1 dichloromethane/methanol/ammonium hydroxide as eluent gave the title compound as a solid (79%) mass spectrum (FAB): M/Z535 (M + H, 100%), 277 (60%).¹H NMR(CDCl₃+CD₃OD, 400MHz, ppm): δ 1.48(d, J ═ 6.8, 3H), 2.52(app t, J ═ 10.4, 1H), 2.85-2.88(m, 2H), 3.47(d, J ═ 2.8, 1H), 3.63(d, J ═ 14.4, 1H), 3.70(dd, J ═ 2.0, 11.6, 1H), 4.24(appt, J ═ 10.8, 1H), 4.35(d, J ═ 2.8, 1H), 4.91(q, J ═ 6.8, 1H), 7.07(app t, J ═ 8.4, 2H), 7.15(s, 2H), 7.37-7.40(m, 2H), 7.65(s, 1H), elemental analysis: calculated value, C₂₃H₂₁F₇N₄O₃: c, 51.69; h, 3.96; n, 10.48; f, 24.88. measurement: c, 51.74; h, 4.04; n, 10.50; f, 24.59. The sample prepared by this method was subsequently identified as form II crystals. It is characterized by a powder X-ray diffraction pattern with critical reflections around: 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9, and 24.8 ° (2 θ).

Example 8Titanocene dimethyl

Titanocene dichloride (Cp) cooled to-5 deg.C (internal temperature) over 1 hour with thorough stirring₂TiCl₂) (249g, 1.00mol) in toluene (2.75L) slurry methyl magnesium Chloride (CH) was added₃MgCl) (750ml, 3.0M THF solution, 2.25mol) while maintaining the temperature below 8 ℃. The resulting orange-yellow slurry was maintained at 0-5 ℃ for 1 hour, or until insoluble purplish red Cp₂TiCl₂And (4) dissolving. NMR analysis was performed to confirm completion of the reaction (see below), and then the reaction solution was poured into 6% ammonium chloride aqueous solution (700ml) while the temperature was maintained at 0-5 ℃. The two layers were separated and the organic phase was washed with cold water (3X 575ml) and brine (575ml) and then Na₂SO₄(220g) And (5) drying. The filtered organic layer was evaporated to 1.5kg (maintaining the internal temperature of 25 ℃ C. or less). By passing¹The H NMR determination of wt.% indicated that the solution contained 187g of product (90%, 12.5 wt.% in toluene/THF). Typically, the material is greater than 95% pure, with only trace amounts of starting material and monomethyl intermediate. The solution was further concentrated to 1.0kg to give an 18 wt% solution in toluene which was easier to analyze. However, the presence of a small amount of THF may increase the stability of the compound. The material was stored in a closed vessel at 0 ℃ under nitrogen atmosphere.¹H NMRCp₂Ti(CH₃)₂：δ6.05(s，10H)，-0.05(s，6H).Cp₂TCl(CH₃)：δ6.22(s，10H)，0.80(s，3H).Cp₂TiCl₂：δ6.56(s，10H).¹⁸C NMR Cp₂Ti(CH₃)₂：δ113.20(Cp2)，45.77((CH₃)₂).Cp₂TiClGH₃：δ115.86(Cp₂)，50.37(CH₃).Cp₂TiCl₂：δ120.18.

Example 94-fluoro-alpha- [ (phenylmethyl) amino]Phenylacetic acid

To a solution of sodium metabisulfite (5.76kg, 30.3mol) in water (50L) was added 4-fluorobenzaldehyde (7.0kg, 56.4mol) and washed with methanol (5L). Sodium cyanide (2.83kg, 57.7mol) was added and washed with water (3L). The reaction was stirred at 25 ℃ for 15 minutes and then cooled to 8 ℃. A solution of benzylamine (6.04kg, 56.4mol) in methanol (11L) was added. The reaction was warmed to 34 ℃ and stirred for 2 hours. Water (23L) was added and extracted with isopropyl acetate (30L). The organic layer was washed with water (2X 10L), followed by saturated aqueous sodium chloride solution (10L), and then evaporated under reduced pressure to give a nitrile compound. It was dissolved in dimethyl sulfoxide (50L). Potassium carbonate (3.27kg, 23.7mol) was added and washed with dimethyl sulfoxide (6L). Aqueous hydrogen peroxide (30%, 9.43L, 83.2mol) was added and stirred at room temperature overnight. Diluted with water (120L) and cooled to 13 ℃. The reaction was filtered and the filter cake was washed with water (50L). The resulting amide compound was dried on a filter and then slurried in commercial methylated spirit (38L). A solution of granular sodium oxychloride (3.27kg, 81.75mol) in water (11L) was added thereto and washed with technical methylated spirit (6L).

After heating to reflux (80 ℃) for 3.5 hours, the reaction was distilled to a small volume while the technical methylated spirit was distilled off. Diluted with water (100L) and extracted with isopropyl acetate (30L). Separating the two layers, and acidifying the water layer to the pH of 5-6 by using concentrated hydrochloric acid. The precipitated solid was filtered and washed with water (2X 10L), then collected and dried in vacuo to give 12.3kg (84% yield based on 4-fluorobenzaldehyde) of 4-fluoro-alpha- [ (phenylmethyl) amino ] phenylacetic acid.

Example 104-fluoro-alpha- [ (phenylmethyl) amino]Phenylacetic acid methyl ester hydrochloride

4-fluoro-. alpha. [ (phenylmethyl) amino ] phenylacetic acid (12.2kg, 47.1mol) was slurried in methanol (37L) and hydrogen chloride gas was passed through the mixture. The obtained slurry is stirred for 3 hours at the temperature of 35-45 ℃, and then is distilled and concentrated to 30-35L. Methyl-t-butyl ether (20L) was added and seeded with methyl 4-fluoro-alpha- [ (phenylmethyl) amino ] phenylacetate hydrochloride. After the formation of the crystal bed, methyl-tert-butyl ether (20L) was added. The slurry was left for 1 hour and then filtered. The filter cake was washed with methyl-t-butyl ether methanol (95: 5, 8.0L) and then dried under vacuum at 30 ℃ to give 12.2kg (84% yield) of methyl 4-fluoro- α - [ (phenylmethyl) amino ] phenylacetate hydrochloride.

Example 11Alpha-amino-4-fluorophenylacetic acid methyl ester

To a slurry of 10% palladium-on-charcoal (1.2kg) in isopropanol (50L) was added methyl 4-fluoro- α - [ (phenylmethyl) amino ] phenylacetate hydrochloride (12.2kg, 39.4 mol). Ammonium formate (5.0kg, 79.4mol) was added and heated to 50 ℃. The progress of the reaction was monitored by HPLC. The reaction was filtered through Hyflo-Supercel and the filter cake was washed with isopropanol (25L). The filtrate was evaporated to a small volume and washed with isopropyl acetate (50L). The residue was dissolved in isopropyl acetate (30L) and washed with 5% potassium phosphate (40L), followed by saturated aqueous sodium chloride (10L). The solution was evaporated in vacuo to give 5.79kg (87% yield) of racemic methyl α -amino-4-fluorophenylacetate. HPLC conditions-column: ZorbaxRx-C8, 25cm × 4.6 mm; column temperature: 40 ℃; mobile phase: acetonitrile: 0.1% aqueous phosphoric acid (70: 30 v/v); flow rate: 1 ml/min; a detector; UV 220 nm; approximate retention time: α -amino-4-fluorophenylacetic acid methyl ester: 2.2 minutes; 4-fluoro- α - [ (phenylmethyl) amino ] phenylacetic acid methyl ester: 2.6 minutes. If unreacted methyl 4-fluoro- α - [ (phenylmethyl) amino ] -phenylacetate (> 2%) remains after 1 hour, 10% palladium-on-carbon (300g) can be slurried in isopropanol (2.0L) 2 times followed by ammonium formate (1.0 kg). Heating was continued until the reaction was complete.

Example 12(S) -alpha-amino-4-fluorophenylacetic acid

A solution of racemic methyl α -amino-4-fluorophenylacetate (3.32kg, 18.2mol) in 96% ethanol (5L) was filtered, and then water (500ml) was added thereto. Further, di-O-benzoyl-D-tartaric acid (DBT, 1.32kg, 3.7mol) in water/ethanol (1: 7, 2.86L) was added. The crystallization mixture was cooled to 5 ℃ and continued for 1.5 hours. The product was collected by filtration, washed with water ethanol (1: 7, 1.1L), air dried and then dried under vacuum at 50 ℃ to give 1.91kg of methyl α -amino-4-fluorophenylacetate, DBT salt (95.8% ee).

The solvent (6.6L) was removed from the liquid by evaporation under reduced pressure. Benzaldehyde (120ml) was added and the solution was stirred and heated at 50 ℃ for 4 hours. The solution was filtered and the solid washed with ethanol (1: 7, 2X 150ml) (chiral HPLC showed the filtrate to contain racemic methyl α -amino-4-fluorophenylacetate). To the filtrate was added a solution of di-O-benzoyl-D-tartaric acid (439g, 1.23mol) in water/ethanol (1: 7, 960ml), then cooled to 5 ℃ for 1.5 hours. The product was collected by filtration, washed with water: ethanol (1: 7, 2X 1.1L), air dried and then dried under vacuum at 50 ℃ to give 1.05kg of methyl α -amino-4-fluorophenylacetate, DBT salt (95.4% ee). The combined yield of alpha-amino-4-fluorophenylacetic acid methyl ester DBT salt was 2.96kg (95% ee). The resolved methyl α -amino-4-fluorophenylacetate, DBT salt, was partitioned between methyl-t-butyl ether (5L) and 5.5M hydrochloric acid (6.2L). The aqueous phase was washed with methyl-tert-butyl ether (5L) and then filtered.

Methyl α -amino-4-fluorophenylacetate DBT salt (2899g, > 95% ee) was partitioned between 5.5M hydrochloric acid (6.2L) and the 2 nd methyl-t-butyl ether extract above. The aqueous phase was re-extracted with methyl-tert-butyl ether (5L) and the filtrate. The aqueous filtrates were combined and concentrated by slow evaporation of the solvent. The reaction was cooled and held at 5 ℃ for 2 hours. The product was collected by filtration and air dried for 30 minutes to give 4.055kg of (S) - α -amino-4-fluorophenylacetic acid, hydrochloride salt (98.7% ee).⁽¹⁾Recrystallization from 5.5M hydrochloric acid (5L) gave (S) - α -amino-4-fluorophenylacetic acid hydrochloride as a wet filter cake (3.28kg, 99.8% ee). The wet cake was heated in a mixture of water (12L) and concentrated hydrochloric acid (375 ml). Concentrated ammonia (1.2L) and water (4L) were added, and then the reaction was cooled to 20 ℃ for overnight. The product was collected by filtration, washed with water (6X 4L), air dried, and then vacuum dried at 50 ℃ for 24 hours to give 1.905kg of (S) -alpha-amino-4-fluoroPhenylacetic acid free base (> 99.7% ee, 48% calculated on racemic methyl α -amino-4-fluorophenylacetate). Chiral HPLC conditions: a chromatographic column: crownpak CR (+), 15cm × 4.5 nm; column temperature: 40 ℃; mobile phase: pH2.0 aqueous perchloric acid solution methanol (95: 5 v/v); flow rate: 1 ml/min; a detector: UV 220 nm; approximate retention time: (R) - α -amino-4-fluorophenylacetic acid: 2.9 minutes; (S) - α -amino-4-fluorophenylacetic acid: 5.6 minutes; (R) - α -amino-4-fluorophenylacetic acid methyl ester: 7.7 minutes; (S) methyl α -amino-4-fluorophenylacetate: 14.0 minutes.

Example 13(S) -4-fluoro-alpha- [ (phenylmethyl) amino]Phenylacetic acid sodium salt

A solution of (S) - α -amino-4-fluorophenylacetic acid (1.00kg, 5.91mol) in dilute sodium hydroxide (1M, 5.91L) was filtered and added to 10% palladium-on-charcoal (25 g). A solution of benzaldehyde (941g, 8.87mol) was added and stirred under a hydrogen atmosphere (50psi) for 4 hours. By filtration, the filtrate was evaporated in vacuo to give a residue, which was washed with ethanol (2X 3L). The residue was slurried in boiling ethanol (1.5L) and cooled to 15 ℃. The slurry was filtered and the filter cake was washed with cold ethanol (2X 500ml) and dried under vacuum at 55 ℃ to give 1.83kg (92% yield) of sodium (S) -4-fluoro- α - [ (phenylmethyl) amino ] phenylacetate.

Example 14(S) -3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinone hydrochloride

To a solution of 1, 2-dibromoethane (4.85kg, 25.8mol) and diisopropylethylamine (419g, 3.25mol) in dimethylformamide (14.7L) was added (S) -4-fluoro-. alpha. [ (phenylmethyl) amino ] phenylacetic acid, sodium salt (850g, 3.02 mol). The reaction was heated at 90 ℃ for 5 hours and then concentrated by vacuum distillation to remove dimethylformamide. The residue was partitioned between ethyl acetate (3.2L) and water (3.2L). The aqueous layer was extracted with 2 nd portion of ethyl acetate (2.0L). The solution was dried over sodium sulfate and then filtered through a pad of silica (1.6 kg). The silica pad was washed with ethyl acetate (8.0L) and the filtrate was evaporated in vacuo. The resulting residue was dissolved in a mixture of isopropanol (1.35L) and ethyl acetate (400ml) and filtered. A solution of hydrogen chloride gas in ethyl acetate (2.44M, 1.34L) was added and the slurry was kept in an ice bath for 1 hour. The slurry was filtered and the filter cake washed with 1: 1 isopropanol ethyl acetate (600ml) followed by methyl-tert-butyl ether (600 ml). The solid was dried in vacuo to give 749g (77% yield, 98% ee) (S) -3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinone hydrochloride. Chiral HPLC conditions: a chromatographic column: chiral (D) -dinitro-benzoylphenyl-glycine (covalent) normal phase, 25cm × 4.6 mm; column temperature: 35 ℃; mobile phase: hexane: ethanol (99: 1 v/v); flow rate: 1 ml/min; a detector: UV 220 nm; approximate retention time: (R) -3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinone: 16 minutes; (S) -3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinone: for 17 minutes.

Example 15Racemization/resolution of 3- (4-fluorophenyl) -4-phenylmethyl-2-morpholinone

To a solution of 3- (4-fluorophenyl) -4-phenylmethyl-2-morpholinone (i.e., N-benzyl-4-fluorophenyl-1, 4-oxazin-2-one) (10g) in isopropyl acetate (110ml) was added a solution of (-) -3-bromocamphor-8-sulfonic acid ((-) -3 BCS) (12g) in acetonitrile (24ml) at room temperature. Crystallization started after 2 to 3 minutes, and the slurry was stirred at room temperature for 1 hour. Trifluoroacetic acid (7ml) was added to the solution, and the mixture was stirred at 65 ℃ for 3 days. The mixture was cooled to 0-5 ℃ for 1 hour, the solid was collected, washed with isopropyl acetate and dried under vacuum at 40 ℃ to give N-benzyl-3- (S) - (4-fluorophenyl) -1, 4-oxazin-2-one (-) -3 BCS salt: yield 17.24g (S) isomer ee was 98.6%. The chiral component of the remaining liquid was determined to be 79% (R), 21% (S). The liquid is stirred at 65 ℃ for 3 days and then cooled to 0-5 ℃. The solid was collected, washed with isopropyl acetate and dried in vacuo to give a further batch of N-benzyl-3- (S) - (4-fluorophenyl) -1, 4-oxazin-2-one (-) -3 BCS salt: yield 0.84g of (S) isomer ee was 98.6%. The chiral component of the remaining liquid was determined to be 64% (R), 36% (S). The liquid was evaporated in vacuo and the residue dissolved in isopropyl acetate (20ml) containing trifluoroacetic acid (1ml) and stirred at 65 ℃ for 20 h. The mixture is cooled to 0-5 ℃ for 1 hour, and the solid is collected, washed with isopropyl acetate and dried under vacuum to give another batch of N-benzyl-3- (S) - (4-fluorophenyl) -1, 4-oxazin-2-one (-) -3 BCS salt: yield 2.2g (S) isomer ee was 99.2%. Total weight of (-) -3 BCS salt: 20.28g, 97% yield. A sample of (-) -3 BCS salt (0.5g) was retained, and the remainder was converted to the free base. The salt was partitioned between isopropyl acetate (50ml) and water (100ml) containing 0.88 ammonia solution (3 ml). The layers were separated and the aqueous phase was extracted with isopropyl acetate (25 ml). The combined organic phases were washed with water (25 ml). The organic phase was concentrated to a residue and washed with isopropyl acetate to give 3- (S) - (4-fluorophenyl) -4-phenylmethyl-2-morpholinone (i.e., N-benzyl-3- (S) - (4-fluorophenyl) -1, 4-oxazin-2-one) as the free base: yield 8.7g, recovery 93% and (S) isomer ee 98.4%.

A further batch of N-benzyl-3- (S) - (4-fluorophenyl) -1, 4-oxazin-2-one (-) -3 BCS salt was prepared essentially following the previous procedure but applying the following amounts and reaction conditions: n-benzyl-3- (4-fluorophenyl) -1, 4-oxazin-2-one (racemate) (4.96 g); a solution of (-) -3 BCS in acetonitrile (1.85M; 9.4 ml); trifluoroacetic acid (2.1 ml); and isopropyl acetate (55 ml). The mixture is stirred at 90 ℃ for 6 days, then cooled to 0-5 ℃ and kept for 1 hour. The solid N-benzyl-3- (S) - (4-fluorophenyl) -1, 4-oxazin-2-one (-) -3 BCS salt was collected and washed with isopropyl acetate (20 ml). Yield 9.40g (90%); the (S) isomer ee was 99.6%. The chiral component of the remaining liquid was determined to be 88% (R), 12% (S).

Example 16(2R-cis) -3, 5-bis (trifluoromethyl) phenylacetic acid 3- (4-fluorophenyl) -4 - (Phenylmethyl) -2-morpholinyl esters

A stirred suspension of (S) -3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinone hydrochloride (2.30kg, 7.15mol) in ethyl acetate (22L) was treated with 10% aqueous sodium bicarbonate (22L). The resulting organic solution was washed with 10% aqueous sodium bicarbonate (11L) and water (2X 11L) in that order, and then dried over 4A molecular sieves (1L) overnight. The solution was evaporated and then washed with tetrahydrofuran (2X 3L) to remove traces of ethyl acetate. The resulting free base (S) -3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinone was dissolved in tetrahydrofuran (19L) and cooled to-75 ℃. L-Selectride (lithium tri-sec-butyl borohydride, 6.74L, 1.06M, 7.15mol) was added thereto while maintaining the temperature below-70 ℃. The reaction was held for 15 minutes then 3, 5-bis (trifluoromethyl) benzoyl chloride (2.57kg, 9.29mol) was added while maintaining the temperature below-70 ℃. The reaction was monitored by HPLC. The reaction was quenched by the addition of acetic acid (205ml) in tetrahydrofuran (800ml) and the reaction was allowed to warm to ambient temperature overnight. The solution was concentrated in vacuo and the resulting oil was diluted with hexane (36L). The reaction was washed with water (17L), 10% aqueous sodium bicarbonate (3X 8.5L) and water (2X 8.5L) in that order, and then dried over 4A molecular sieves (1L) overnight. The reaction was analyzed by HPLC to contain 2.44kg (yield 65%) (2R-cis) -3, 5-bis (trifluoromethyl) phenylacetic acid 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl ester. This batch was combined with another batch of 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl (2R-cis) -3, 5-bis (trifluoromethyl) phenylacetate prepared before (0.59kg, measured in 7L hexane). The combined two batches were filtered through a 20 μm filter and then diluted with hexane (9L). The crude 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl (2R-cis) -3, 5-bis (trifluoromethyl) phenylacetate solution (assay 3.03kg, 5.74mol) was treated with a solution of hydrochloric acid in diethyl ether (9.6L, 1.0M) to give a white precipitate of 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl (2R-cis) -3, 5-bis (trifluoromethyl) phenylacetate hydrochloride (hydrochloride formed to remove the tri-sec-butylborane residue (from L-selecteide)). The solid was collected by filtration, washed with hexane (2X 8L) and then dried under chlorine. The hydrochloride salt of the product was broken up by slurrying in a mixture of toluene (36L) and 10% aqueous sodium bicarbonate (13 ml). The resulting organic solution was washed with 10% aqueous sodium bicarbonate (13L) and water (2X 18L). The toluene solution was measured to contain 3.00kg of 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl (2R-cis) -3, 5-bis (trifluoromethyl) -phenylacetate, 80% by area, corrected for p-toluene). The toluene solution was stored over 4A molecular sieves (1L). HPLC conditions: a chromatographic column: zorbax RX-C8, 25cm × 4.6mm, mobile phase: acetonitrile: 0.1% aqueous phosphoric acid (75: 25 v/v); flow rate: 1.5 ml/min; a detector: UV 220 nm; approximate retention time: reduced (S) -3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinone: 1.6 minutes; (S) -3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinone: 3.3 minutes; (2R-cis) -3, 5-bis (trifluoromethyl) phenylacetic acid 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl ester: 9.2 minutes.

Example 17(2R-cis) -2- [ [1- [3, 5-bis (trifluoromethyl) phenyl ] phenyl]Vinyl radical]Oxy radical] -3- (4-fluorophenyl) -4- (phenylmethyl) morpholine

A solution of 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl (2R-cis) -3, 5-bis (trifluoromethyl) phenylacetate (1.60kg, 3.02mol) in toluene was evaporated and purged with nitrogen. Tetrahydrofuran (1.6L) was added followed by a toluene solution of titanocene dimethyl (8.35 wt%, 1.73kg reagent, 8.31mol) (prepared as described below). The reaction was stirred with nitrogen for 25 minutes and then heated to 80 ℃. At 80 ℃ in the dark for 5 hours, then cool to ambient temperature and hold overnight. The batch of solvent was converted to heptane by vacuum distillation while maintaining the temperature below 20 deg.c (126L of heptane was added with 120L of distillate) (the reaction mixture was solvent converted to heptane and treated with bicarbonate buffered peroxide to precipitate a titanium residue). To the cooled (7 ℃ C.) mixture was added water (22L), sodium bicarbonate (2.0kg), followed by 30% hydrogen peroxide (3.5L). The reaction was stirred at ambient temperature overnight. The two phases partition while a large amount of titanium residue remains in the aqueous phase. The aqueous phase was back-extracted with heptane (10L), and the combined organic phases were filtered, washed with water (2X 4L), and concentrated. The crude product was recrystallized by dissolving in hot methanol (17L), cooling to ambient temperature, and then adding water (1.8L). The material was isolated by filtration at 0 ℃. The filter cake was washed with 10% aqueous methanol (2L, 0 deg.C) and the solid was then dried under nitrogen at ambient temperature (1.45kg of 94% by weight pure (2R-cis) -2- [ [1- [3, 5-bis (trifluoromethyl) phenyl ] vinyl ] oxy ] -3- (4-fluorophenyl) -4- (phenylmethyl) morpholine).

The dimethyltitanocene reagent can be prepared according to the following formulaThe preparation method comprises the following steps. To a cooled (-8 ℃ C.) well stirred slurry of titanocene dichloride (3.35kg, 13.5mol) in methyl-tert-butyl ether (13.4L) was added a solution of methyllithium (590g, 26.9mol) in diethyl ether (4.38% w/w, 13.5kg) while maintaining the temperature below 5 ℃. The resulting slurry was held at 0-5 ℃ for 1 hour. Water (8L) was added to stop the reaction while maintaining the temperature at 0-8 ℃. The organic phase was washed with cold water (4X 3L). While maintaining the temperature at 25 ℃ or lower, the organic layer was converted to toluene by distillation with the addition of toluene (24L). By passing¹The weight% determination by H NMR showed that the solution contained 1.75kg of titanocene dimethyl (yield 63%, 8.35 wt% in toluene). The material was stored at 0 ℃ under nitrogen atmosphere. Subsequently use¹H NMR followed the progress of the reaction. (250MHz, CDCl)₃With a 10 second delay between pulse waves).

Cp₂TiMe₂：*(ppm)6.05(s，10H)，-0.05(s，6H)；Cp₂TiClMe：*6.22(s，10H)，0.80(s，3H)；Cp₂TiCl₂：*6.56(s，10H).

The dimethyltitanocene reagent can also be prepared as follows. Titanium Dichlorotitanocene (Cp) cooled to-5 ℃ and stirred well in 10 minutes₂TiCl₂) (6.0g, 24.1mmol) in a slurry of toluene (72ml) was added dropwise methyl magnesium Chloride (CH)₃MgCl) (19.8g, 19.2ml, 3.0M in THF, 57.6mmol, 2.4 equivalents) while maintaining the temperature below 5 ℃. A viscous slurry is formed when the magnesium chloride precipitates. The resulting slurry was held at 0-5 ℃ for 50 minutes with insoluble red Cp₂TiCl₂And (4) dissolving. The reaction was completed by NMR measurement of the reaction-terminated sample. 0.2ml of sample was poured into 1ml of water and 1ml of CDCl₃. The chloroform layer was used directly for NJR analysis. Titanocene dimethyl at 6.0ppm (Cp group) and-0.2 ppm (CH)₃Group) has a resonance spectrum. The monomethyl compound has a low magnetic field resonance spectrum at 0.2-0.3ppm, and titanocene dichloride has a resonance spectrum at 6.5 ppm. The reaction was then quenched by the addition of 10% aqueous ammonium chloride (20ml) over 10 minutes and the temperature was maintained below 10 ℃. The layers were separated and the organic phase was washed with cold water (3X 20ml) and brine (20ml) and thenThrough Na₂SO₄(20g) And (5) drying. The filtered organic layer was concentrated in vacuo to about half volume. The total weight of the solution was 43g and NMR analysis showed 11.2 wt% titanocene dimethyl (4.8g, 96% yield). The THF content was 2%, however, the presence of a small amount of THF increased the stability of the reagent. The material was stored at 0 ℃ under a chlorine atmosphere.

In addition, the dimethyltitanocene reagent can be prepared as follows. To a slurry of titanocene dichloride (249g, 1.00mol) in toluene (2.75L) cooled to-5 deg.C (internal temperature) and stirred well was added MeMgCl (750ml, 3.0M THF solution, 2.25mol) over 1 hour while maintaining the temperature below 8 deg.C. The resulting orange-yellow slurry was maintained at 0-5 ℃ for 1 hour, or until insoluble purplish red Cp₂TiCl₂And (4) dissolving. NMR analysis confirmed that the reaction was complete (see below) and was stopped by adding 6% aqueous ammonium chloride (700ml) while maintaining 0-5 ℃. The organic phase was washed with cold water (3X 575ml) and brine (575ml) and then Na₂SO₄(220g) And (5) drying. The filtered organic layer was evaporated to 1.5kg (maintaining the internal temperature of 25 ℃ C. or less). Warp beam¹The H NMR determination of wt% indicated that the solution contained 187g of product (90%, 12.5 wt% toluene/THF solution). Typically, the material is greater than 95% pure, with only trace amounts of starting material and monomethyl intermediate. This solution can be further concentrated to 1.0kg to give an 18 wt% toluene solution which can be analyzed relatively easily. However, the presence of a small amount of THF may increase the stability of the reagent. The material was stored in a closed vessel at 0 ℃ under nitrogen atmosphere.¹H NMR Cp₂TiMe₂：δ6.05(s，10H)，-0.05(s，6H).Cp₂TiClMe：δ6.22(s，10H)，0.80(s，3H).Cp₂TiCl₂：δ6.56(s，10H).¹³C NMR Cp₂TiMe₂：δ113.20(Cp₂)，45.77(Me₂).Cp₂TiClMe：δ115.86(CP₂)，50.37(Me).Cp₂TiCl₂：δ120.18.

HPLC conditions: a chromatographic column: zorbax RX-C8, 25cm × 4.6 mm; mobile phase: acetonitrile: 0.1% aqueous phosphoric acid (65: 35 v/v); flow rate: 1.5 ml/min; a detector: UV 220 nm; approximate retention time: (2R-cis) -2- [ [1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] oxy ] -3- (4-fluorophenyl) -4- (phenylmethyl) morpholine: 17.2 minutes; (2R-cis) -3, 5-bis (trifluoromethyl) -phenylacetic acid 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl ester: and 18.9 minutes.

Example 18

(2R-cis) -2- [ [1- [3, 5-bis (trifluoromethyl) phenyl ] phenyl]Vinyl radical]Oxy radical] -3- (4-fluorophenyl) -4- (phenylmethyl) morpholine

A toluene solution containing 2.99kg (5.67mol) of 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl (2R-cis) -3, 5-bis (trifluoromethyl) phenylacetate [ i.e. (4-benzyl-2- (R) - (3, 5-bis (trifluoromethyl) benzoyloxy) -3- (S) (4-fluorophenyl) -1, 4-oxazine ] was evaporated in a 100L flask, the flask was purged with nitrogen, then tetrahydrofuran (25L) was added, followed by toluene/THF solution of titanocene dimethyl (12.5 wt%, 4.2kg reagent, 20.2mol) and a yellow orange solution was purged with nitrogen for 25 minutes, then heated to 80 ℃ the reaction was in the dark for 4 hours and cooled to ambient temperature methanol (11.6L) and water (1.9L) were added, the mixture was heated at 40 ℃ overnight to precipitate a titanium residue as a green solid. After cooling to ambient temperature, the solid was removed by filtration, the filter cake was washed with toluene and the resulting mother liquor was evaporated. The crude product was dissolved in hot methanol (30L), cooled to ambient temperature and recrystallized by the addition of water (3.4L) over 3 hours. The material was isolated by filtration at 0 deg.C, the filter cake was washed with 0 deg.C 10% aqueous methanol (2L) and the solid was dried at ambient temperature under nitrogen to give 2.55kg of (2R-cis) -2- [ [1- [3, 5-bis (trifluoromethyl) phenyl ] ethenyl ] oxy ] -3- (4-fluorophenyl) -4- (phenylmethyl) morpholine (85%).

Example 19[2R-[2a(R ^* )，3a]]-2- [1- [3, 5-bis (trifluoromethyl) phenyl]Ethoxy radical]-3 - (4-fluorophenyl) morpholine-4-methylbenzenesulfonate

(2R-cis) -2- [ [1- [3, 5-bis (trifluoromethyl) phenyl ] phenyl]Vinyl radical]Oxy radical]A1: 1 ethyl acetate/ethanol (13L) solution of-3- (4-fluorophenyl) -4- (phenylmethyl) morpholine (1082g, 94% pure, 1.94mol) was combined with 10% palladium on charcoal (165 g). The resulting slurry was purged with hydrogen (40psi, 20-25 deg.C) for 12 hours. The reaction was monitored by hydrogen uptake and HPLC. The vessel was vented and the catalyst was filtered off. The catalyst, after washing with 1: 1 ethyl acetate: ethanol (6L), followed by ethyl acetate (2L), contained crude [2R- [2a (R)^*)，3a]]-2- [1- [3, 5-bis (trifluoromethyl) phenyl]Ethoxy radical]The combined organic phases of (E) -3- (4-fluorophenyl) morpholine were concentrated in vacuo. The second batch was dosed with 1078g of (2R-cis) -2- [ [1- [3, 5-bis (trifluoromethyl) phenyl ] methyl ] phenyl]Vinyl radical]Oxy radical]-3- (4-fluorophenyl) -4- (phenylmethyl) morpholine (1.93mol) was prepared as starting material. The resulting crude [2R- [2a (R) ]^*)，3a]]-2- [1- [3, 5-bis (trifluoromethyl) phenyl]Ethoxy radical]-3- (4-fluorophenyl) morpholine was concentrated in vacuo and combined with the first crop. Two combined batches of crude [2R- [2a (R)^*)，3a]]-2- [1- [3, 5-bis (trifluoromethyl) phenyl]Ethoxy radical]-3- (4-fluorophenyl) morpholine was washed with methyl-t-butyl ether (2X 3L) to remove residual ethyl acetate and ethanol, and then dissolved in methyl-t-butyl ether (3L). The solution was analyzed to contain 1348g (3.09mol, yield 80%) [2R- [2a (R-)^*)，3a]]-2- [1- [3, 5-bis (trifluoromethyl) phenyl]Ethoxy radical]-3- (4-fluorophenyl) morpholine (as the free base). Another method is 60g of vinyl ether, 650ml of methyl tert-butyl ether (MTBE), and 18g of 5% palladium-alumina, stirred at 40 ℃ for 12 hours under 40psi of hydrogen. Yield was found to be 87%, diastereomer in a ratio of 91: 9. At the end of the reaction, the catalyst was removed by filtration through Solka-Floc, and the filtrate was concentrated to 140 ml.

The first batch was treated with a warm (40 ℃) solution of p-toluenesulfonic acid monohydrate (575g, 3.03mol) in methyl-tert-butyl ether (3.2L). During the addition period [2R- [2a (R)^*)，3a]]-2- [1- [3, 5-bis (trifluoromethyl) phenyl]Ethoxy radical]Crystallization of p-toluenesulfonate salt of (E) -3- (4-fluorophenyl) morpholine was started. The batch was cooled to ambient temperature and hexane (24L) was added. The batch was held for 2 hours and the product was collected by filtration. The solid was washed with 4: 1 hexane: methyl-tert-butyl ether (2X 2.5L)Then dried under nitrogen (1761g (1655 g) corrected purity) [2R- [2a (R)^*)，3a]]-2- [1- [3, 5-bis (trifluoromethyl) phenyl]Ethoxy radical]-3- (4-fluorophenyl) morpholine 4-methylbenzenesulfonate in a purity of 94% by weight in a yield of 70%). Alternatively, 16.0g p-TsOH monohydrate in 64ml of MTBE was added to the second batch over 20 minutes at 35 ℃. The crystallized p-toluenesulfonate was a thick slurry. 520ml of hexane are then added over 1 hour and the slurry is stirred at ambient temperature for 2 hours. The slurry was filtered, washed with 2X 60ml of 1: 4 MTBE: hexane and dried under vacuum to give 51.9g of p-toluenesulfonate salt containing 0.9% of the undesired diastereomer (75% yield). HPLC conditions: a chromatographic column: zorbax RX-C18, 25cm × 4.6 mm; mobile phase: acetonitrile: 0.005M aqueous sodium heptanesulfonate, 0.002M potassium dihydrogen phosphate, 0.0005M disodium hydrogen phosphate (75: 25, v/v); flow rate: 1.5 ml/min; a detector: UV 220 nm; approximate retention time: [2R- [2a (R)^*)，3a]]-2- [1- [3, 5-bis (trifluoromethyl) phenyl]Ethoxy radical]-3- (4-fluorophenyl) morpholine: 4.5 minutes; n-benzyl [2R- [2a (R)^*)，3a]]-2- [1- [3, 5-bis (trifluoromethyl) phenyl]Ethoxy radical]-3- (4-fluorophenyl) morpholine: 25.0 minutes; (2R-cis) -2- [ [1- [3, 5-bis (trifluoromethyl) phenyl ] phenyl]Vinyl radical]Oxy radical]-3- (4-fluorophenyl) -4- (phenylmethyl) morpholine: 30.0 minutes. HPLC conditions: a chromatographic column: ZorbaxRX-C18, 25cm × 4.6 mm; mobile phase: acetonitrile: 0.005M aqueous sodium heptanesulfonate, 0.002M potassium dihydrogen phosphate, 0.0005M disodium hydrogen phosphate (60: 40 v/v); flow rate: 1.5 ml/min; a detector: UV 220 nm; approximate retention time: [2R- [2a (R)^*)，3a]]-2- [1- [3, 5-bis (trifluoromethyl) phenyl]Ethoxy radical]-3- (4-fluorophenyl) morpholine: 9.0 minutes; diastereomer [2R- [2a (R)^*)，3a]]-2- [1- [3, 5-bis (trifluoromethyl) phenyl]Ethoxy radical]-3- (4-fluorophenyl) morpholine: 11.0 min (methyl position epimerization).

Example 20[2R-[2a(R ^* )，3a]]-5- [ [2- [ - [ 3.5-bis (trifluoromethyl) phenyl ] phenyl]Ethoxy radical Base of]-3- (4-fluorophenyl) -4-morpholinyl]Methyl radical]-1, 2-dihydro-3H-1, 2, 4 -triazol-3-ones

To [2R- [2a (R) ]^*)，3a]]-2- [1- [3, 5-bis (trifluoromethyl) phenyl]Ethoxy radical]To a solution of-3- (4-fluorophenyl) morpholine 4-methylbenzenesulfonate (1254g, 2.06mol), N-methylcarboxyl-2-chloroacetamidinohydrazone (375g, 2.26mol) and dimethylformamide (10L) was added powdered potassium carbonate (682g, 4.93 mol). The reaction is maintained at 15-25 ℃ for 2.5 hours. The reaction was diluted with 1: 1 hexane: methyl-t-butyl ether (10L) and 10.9% aqueous ammonium chloride (11L). The phases were partitioned and the aqueous phase was back-extracted with 1: 1 hexane: methyl-tert-butyl ether (2X 8L) followed by 1: 2 hexane: methyl tert-butyl ether (8L). The combined organic phases were washed with water (2X 15L) and then concentrated in vacuo. The resulting material was dissolved in xylene (20L) and heated to reflux (137 ℃ C.). The solution is maintained at reflux for 3 hours, cooled to ambient temperature and then crystallized to give [2R- [2a (R)^*)，3a]]-5- [ [2- [1- [3, 5-bis (trifluoromethyl) phenyl ] phenyl]Ethoxy radical]-3- (4-fluorophenyl) -4-morpholinyl]Methyl radical]-1, 2-dihydro-3H-1, 2, 4-triazol-3-one. The batch was kept overnight and then filtered. The filter cake was washed with xylene (2L) and then hexane (2X 2L), and then dried under vacuum at 30 ℃ for 3 days to obtain [2R- [2a (R)^*)，3a]]-5- [ [2- [1- [3, 5-bis (trifluoromethyl) phenyl ] phenyl]Ethoxy radical]-3- (4-fluorophenyl) -4-morpholinyl]Methyl radical]-1, 2-dihydro-3H-1, 2, 4-triazol-3-one [ i.e. 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazol) methylmorpholine]696g, yield 63%.

Alternatively, the title product may be obtained from the amine TsOH salt (1.90kg, 3.12 mol); n-methylcarboxyl-2-chloroacetamidinohydrazone (516.3g, 3.12 mol); k₂CO₃(1.08kg, 2.5 equivalents); and DMSO (15.6L) preparation: to amine salts and powdery K at 20 deg.C₂CO₃To the DMSO (7.8L) suspension was added a solution of N-methylcarboxyl-2-chloroacetamidinohydrazone in DMSO (7.8L). Half of the solution was added first quickly, cooled slightly with an ice-water bath, and then the remaining half was added over 1 hour. After the addition was complete, the reaction was checked by LC and quenched by the addition of cold water (15L) and a solution of methyl tert-butyl ether (MTBE) (30L). The organic layer was separated and successively washed with water and saturated NaHCO₃And washed with brine (20L/time). The aqueous layer was treated with additional MTBE (15)L) back extraction. The combined MTBE solution was concentrated to an oil. The resulting crude product was dissolved in xylene (25L) and diisopropylethylamine (6.25L) and heated to reflux (about 135 ℃ C.) and the reaction monitored by LC. The reaction was allowed to proceed for 4-6 hours, the reaction solution was cooled to room temperature overnight, and filtered to give the title product (expected to be 1.33kg, about 80%, with a typical purity of 98.5A%). The crude product was dissolved in hot methanol (13.3L) and charcoal 133g was added, followed by filtration and the charcoal was washed with hot methanol (3.3L). The methanol solution was cooled to room temperature and then water (7L) was added dropwise. After stirring at room temperature for 2 hours, the suspension was filtered to isolate the purified product (i.e., 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine) as a white crystalline compound (expected 1.20kg, 90% recovery, general 99.5A% purity, HPLC conditions: column of color spectrum: zorbax RX-C8, 25cm × 4.6mm, mobile phase: (A) acetonitrile, (B) 0.1% aqueous phosphoric acid solution, linear gradient: within 10 minutes, the ratio of 40: 60A: B to 70: 30A: B, the flow rate: 1.5 ml/min, detector: UV 220nm, approximate retention time: alkylated intermediates: 5.7 minutes; [2R- [2a (R).^*)，3a]]-5- [ [2- [1- [3, 5-bis (trifluoromethyl) phenyl ] phenyl]Ethoxy radical]-3- (4-fluorophenyl) -4-morpholinyl]Methyl radical]-1, 2-dihydro-3H-1, 2, 4-triazol-3-one: 8.2 minutes. The sample prepared by this method was subsequently identified as form II crystals. It is characterized by a powder X-ray diffraction pattern with a key reflection of about: 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9, and 24.8 ° (2 θ).

Example 21Preparation of form I2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy 3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-) 1, 2, 4-triazole) methylmorpholine

Form II 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine was vortexed in isopropyl acetate at 25 ℃ to produce form I2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine, which was subsequently isolated by filtration as a solid.

Similarly, 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine form II can be vortexed in ethanol, 2-propanol, water, methanol/water mixture or acetonitrile at 25 deg.C to produce 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine form I, the resulting solid was then isolated by filtration.

Example 22Preparation of form I seed 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) Ethoxy) -3- (S) - (4-fluoro) phenyl-3- (3- (5-oxo-1H, 4H) -1, 2, 4-triazole) methylmorpholine

A sample of form II 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine was placed in a small aluminum pan, the unsealed pan was placed in a differential scanning calorimetry cell apparatus the sample was heated from ambient temperature to 230 ℃ and then cooled back to room temperature the resulting solid was used to prepare form I2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H on a large scale, the use as seed crystals in 4H-1, 2, 4-triazole) methylmorpholine is suitable.

Example 23Preparation of form I2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) Ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H) -1, 2, 4-triazole) methylmorpholine

Form II 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine (566g) and 5.7L methanol were added to a 22L flask the mixture was heated to reflux (65 ℃ C.) during which time all solids were dissolved in the solution, the solution was cooled to 50 ℃ C. and treated with approximately 200mg of form I2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine, cooled to 45 ℃ during which a crystal bed is formed. The mixture was cooled to 26 ℃ during which time 2.8L of water was added over 1 hour. The mixture was held at room temperature for 2 hours and then heated to 70 ℃ for 2 hours to ensure complete conversion of all form II species to form I. The mixture was cooled overnight, allowed to cool to 0 ℃ for 70 minutes at 0 ℃ and then filtered at-3 ℃. The collected material was dry overnight on a nitrogen tent on the filter and dry packaged to yield 549g (97%).

Example 24Preparation of form I2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) Ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H) -1, 2, 4-triazole) methylmorpholine

2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine form II (14.5kg) and 158L methanol were added to a pilot scale reaction vessel, the mixture was heated to 50 ℃ during which time all compounds dissolved, 6kg of methanol slurry of activated carbon (Darco G-60) (1.5kg) was added through the sight glass and rinsed with another 2L of methanol, the batch was heated to reflux (62 ℃) for 1 hour then cooled to 60 ℃ and filtered through a 14' SS flash filter (Sparkler) after 10 minutes, no abnormalities were observed on the sight glass, the recycle line was returned to the reactor. Then through a flash filter, then through sequentially assembled 10 μ and 0.6 μ filters, and finally collected in a container. The line was transferred and 50L was added to the last reactor as a flush. The circulation rinse was performed for 10 minutes to clean the circulation line and warm to above room temperature. And then transferred through the filter into a receiving vessel. The mixture was concentrated from 210L to 170L by atmospheric distillation. The sample showed that a hipped concentration of 88g/L (14.9kg, no loss) had been achieved. The concentrate was cooled to 50 ℃. And seeded with 300g of pure form I2- (R) - (1- (R) -3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine. A very bright seed layer was formed, but crystallization hardly precipitated even at 45 ℃. The diluted slurry was kept at 45 ℃ for 1 hour with no change in appearance. The diluted slurry was allowed to cool to 25 ℃ overnight to give a slurry with 60.5g/L of the compound dissolved. The wet cake sample shows only form I crystals. 83.6kg of water (33% by volume of methanol) were then added via the subsurface feed tube over a period of 3 hours. The sample showed 0.1 wt% of the desired compound in the supernatant and all crystals were form I. The batch was cooled to 0 ℃ for 2 hours. The batch was then transferred to a mass-produced filter in one go. The vessel was washed with about 15kg of methanol/water (2/1) cake wash to provide an additional 1000g of product. The remaining 15kg of cake wash was charged to the filter via a nozzle. 217.8kg of mother liquor and detergent (containing 0.1% by weight of the desired compound) were collected. The wet cake (14.8kg) was dried overnight at 50 ℃ under 27.5 "vacuum using a vacuum machine with 0.2 SCFM. After 12 hours, TG (thermogravimetric analysis) showed a loss of 0.0%. This batch gave a total weight of 12.82kg of the title compound.

Example 25

Exemplary pharmaceutical compositions containing the Compounds of the invention A： Hard capsule containing 5mg of active ingredient

Composition (I) The amount of each capsule (mg)

Active ingredient 5

Lactose 194

Magnesium stearate 1

Capsule No. 1 200

The active ingredient is sieved through a No. 60 sieve to form a powder, and then the lactose and magnesium stearate are pressed through a No. 60 press filter cloth to form a powder. The ingredients were mixed for about 10 minutes and filled into hard gelatin capsules No. 1.B： Tablet formulation

A typical tablet contains the active ingredient (5mg), pregelatinized starch USP (82mg), microcrystalline cellulose (82mg) and magnesium stearate (1 mg).

While the invention has been described and illustrated in detail with respect to certain specific embodiments thereof, it will be apparent to those skilled in the art that various modifications, changes, improvements, substitutions, deletions, or additions may be made to the methods and protocols without departing from the spirit and scope of the invention. For example, as a variation, an effective amount other than the specific amounts described above may be appropriate for the mammal to be treated for any of the indications with the compounds of the invention described above. Likewise, the particular pharmacological responses observed may vary depending upon the particular active compounds selected or whether a pharmaceutically acceptable carrier is employed, as well as the dosage form and mode of administration, and such expected results vary or are different, depending upon the objectives and practices of the present invention. Accordingly, the invention is to be determined by the scope of the claims, which are to be interpreted as broadly as is reasonable.

Claims

1. Form I crystals of the compound 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine are essentially characterized by a powder X-ray diffraction pattern showing key reflections at about 12.0, 15.3, 16.6, 17.0, 17.6, 19.4, 20.0, 21.9, 23.6, 23.8 and 24.8 ° (2 Θ).

2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the crystal of claim 1.

3. Use of the crystal according to claim 1 for the preparation of a medicament for antagonizing the effect of substance P at the receptor site or for the blockade of neurokinin-1 receptors in a mammal.

4. Use of the crystal according to claim 1 for the preparation of a medicament for the treatment or prevention of: diabetic neuropathy, peripheral neuropathy, AIDS related neuropathy, chemotherapy induced neuropathy, and neuralgia.

5. Use of the crystal according to claim 1 for the preparation of a medicament for the treatment or prevention of emesis in a mammal.

6. Use of the crystal according to claim 1 for the preparation of a medicament for the treatment or prevention of a central nervous system disorder in a mammal.

7. Use of the crystal according to claim 1 for the preparation of a medicament for the treatment or prevention of depression in a mammal.

8. The use according to claim 7, wherein the prepared medicament is effective in alleviating the condition when used in combination with an antidepressant.

9. Use of the crystal according to claim 1 for the preparation of a medicament for the treatment or prevention of anxiety in a mammal.

10. The use according to claim 9, wherein the medicament is formulated for use with an anxiolytic agent effective to alleviate a condition thereof.

11. Use of the crystal according to claim 1 for the preparation of a medicament for treating or preventing schizophrenia in a mammal.

12. The use according to claim 11, wherein the medicament is formulated for use with an antipsychotic agent to effectively alleviate a condition thereof.

13. A process for preparing the crystalline form I2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine of claim 1, which comprises contacting form II 2- (R) - (1-R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine in a solvent selected from the group consisting of ethanol, 2-propanol, methanol, ethanol, acetonitrile and isopropyl acetate.

14. A process for preparing 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine form I crystals as claimed in claim 1, which process comprises:

heating a sample of 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine with an optional morphological composition to a temperature of 215-230 ℃, and then

The sample was allowed to return to ambient temperature.

15. The method of claim 14, wherein the starting 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine form is form II.

16. A process for preparing 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine form I crystals as claimed in claim 1, which process comprises:

suspending 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine in a methanol/water mixture;

stirring the resulting mixture at about 0-50 ℃ for a time sufficient to form 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine I;

17. The method of claim 16, wherein the starting form of 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine is form II.

18. A crystalline form of the compound 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine characterized by a powder X-ray diffraction pattern showing critical reflections at about 12.0, 15.3, 16.6, 17.0, 17.6, 19.4, 20.0, 21.9, 23.6, 23.8 and 24.8 ° (2 θ) and wherein there is substantially no 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, another crystalline form of 4H-1, 2, 4-triazole) methylmorpholine characterized by a powder X-ray diffraction pattern showing key reflections at about 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9 and 24.8 ° (2 Θ).

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline form of the compound 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2, 4-triazole) methylmorpholine, the crystalline form characterized by a powder X-ray diffraction pattern showing critical reflections at about 12.0, 15.3, 16.6, 17.0, 17.6, 19.4, 20.0, 21.9, 23.6, 23.8 and 24.8 ° (2 θ) and wherein there is substantially no 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H) Another crystalline form of 4H-1, 2, 4-triazole) methylmorpholine characterized by a powder X-ray diffraction pattern showing key reflections at about 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9 and 24.8 ° (2 θ).