Bupropion metabolites and methods of their synthesis and use

Abstract

Methods and compositions are disclosed which utilize metabolites of bupropion for treating disorders ameliorated by inhibition of neuronal monoamine reuptake. Such disorders include, but are not limited to, sexual dysfunction, affective disorders, cerebral function disorders, cigarette smoking, and incontinence. Methods of making optically pure bupropion metabolites are also disclosed.

What is claimed is:  
     
         1 . A method of treating or preventing a disorder that is ameliorated by the inhibition of neuronal monoamine reuptake which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a bupropion metabolite, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         2 . The method of  claim 1  wherein the bupropion metabolite is optically pure.  
     
     
         3 . The method of  claim 2  wherein the optically pure bupropion metabolite is (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (R,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-t -ol; (S,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone; or (S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone.  
     
     
         4 . The method of  claim 3  wherein the optically pure bupropion metabolite is optically pure (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morphinol.  
     
     
         5 . The method of  claim 1  wherein adverse effects associated with the administration of racemic bupropion are reduced or avoided.  
     
     
         6 . The method of  claim 1  wherein the bupropion metabolite, or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof, is adjunctively administered with a second pharmacologically active compound.  
     
     
         7 . The method of  claim 6  wherein the second pharmacologically active compound is selected from the group consisting of selective serotonin reuptake inhibitors, 5-HT 3  inhibitors, and nicotine.  
     
     
         8 . A method of treating or preventing sexual dysfunction which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a bupropion metabolite, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         9 . The method of  claim 8  wherein the patient is male.  
     
     
         10 . The method of  claim 9  wherein the sexual dysfunction is erectile dysfunction.  
     
     
         11 . The method of  claim 8  wherein the patient is female.  
     
     
         12 . The method of  claim 8  wherein the bupropion metabolite is optically pure.  
     
     
         13 . The method of  claim 8  wherein the optically pure bupropion metabolite is (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (R,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone; and (S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone.  
     
     
         14 . The method of  claim 13  wherein the optically pure bupropion metabolite is optically pure (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol.  
     
     
         15 . The method of  claim 8  wherein the bupropion metabolite, or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof, is administered orally, transdermally, or mucosally.  
     
     
         16 . The method of  claim 8  wherein the bupropion metabolite, or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof, is adjunctively administered with a 5-HT 3  antagonist.  
     
     
         17 . The method of  claim 16  wherein the 5-HT 3  antagonist is an antiemetic agent.  
     
     
         18 . The method of  claim 17  wherein the 5-HT 3  antagonist is selected from the group consisting of granisetron, metoclopramide, ondansetron, renzapride, zacopride, norcisapride, tropisetron, and optically pure stereoisomers, active metabolites, and pharmaceutically acceptable salts, hydrates, solvates, hydrates, and clathrates thereof.  
     
     
         19 . A method of treating or preventing an affective disorder which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a bupropion metabolite, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         20 . The method of  claim 19  wherein the bupropion metabolite is optically pure.  
     
     
         21 . The method of  claim 20  wherein the optically pure bupropion metabolite is (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (R,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone; or (S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone.  
     
     
         22 . The method of  claim 21  wherein the optically pure bupropion metabolite is optically pure (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morphinol.  
     
     
         23 . The method of  claim 19  wherein adverse effects associated with the administration of racemic bupropion are reduced or avoided.  
     
     
         24 . The method of  claim 19  wherein the bupropion metabolite, or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof, is adjunctively administered with a therapeutically or prophylactically effective amount of a second pharmacologically active compound.  
     
     
         25 . The method of  claim 24  wherein the second pharmacologically active compound is selected from the group consisting of selective serotonin reuptake inhibitors, 5-HT 3  inhibitors, and nicotine.  
     
     
         26 . The method of  claim 19  wherein the affective disorder is depression.  
     
     
         27 . The method of  claim 19  wherein the affective disorder is narcolepsy.  
     
     
         28 . The method of  claim 19  wherein the affective disorder is nicotine addiction.  
     
     
         29 . A method of treating or preventing a cerebral function disorder which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a bupropion metabolite or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         30 . The method of  claim 29  wherein the bupropion metabolite is optically pure.  
     
     
         31 . The method of  claim 29  wherein the optically pure bupropion metabolite is (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (R,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R)-1-(3-chlorophenyl)-2-[(1,1,-dimethylethanol)amino]-1-propanone; or (S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-prop anone.  
     
     
         32 . The method of  claim 31  wherein the optically pure bupropion metabolite is optically pure (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morphinol.  
     
     
         33 . The method of  claim 29  wherein the bupropion metabolite, or pharmaceutically acceptable salt, solvate, or clathrate thereof, is administered orally, transdermally, or mucosally.  
     
     
         34 . The method of  claim 29  wherein the bupropion metabolite, or pharmaceutically acceptable salt, solvate, hydrate or clathrate thereof is adjunctively administered with a therapeutically or prophylactically effective amount of a second pharmacologically active compound.  
     
     
         35 . The method of  claim 29  wherein the cerebral function disorder is Parkinson's disease.  
     
     
         36 . The method of  claim 29  wherein the cerebral function disorder is epilepsy.  
     
     
         37 . The method of  claim 29  wherein the cerebral function disorder is Alzheimer's disease.  
     
     
         38 . The method of  claim 29  wherein the cerebral function disorder is dementia.  
     
     
         39 . A method of eliciting smoking cessation which comprises administering to a patient in need thereof a therapeutically effective amount of a bupropion metabolite, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         40 . The method of  claim 39  wherein the bupropion metabolite is optically pure.  
     
     
         41 . The method of  claim 39  wherein the optically pure bupropion metabolite is (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (R,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone; or (S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone.  
     
     
         42 . The method of  claim 41  wherein the optically pure bupropion metabolite is optically pure (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol.  
     
     
         43 . The method of  claim 39  wherein the bupropion metabolite, or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof, is administered orally, mucosally, or transdermally.  
     
     
         44 . The method of  claim 43  wherein the bupropion metabolite, or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof, is administered transdermally.  
     
     
         45 . The method of  claim 39  wherein the bupropion metabolite, or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof, is adjunctively administered with a therapeutically effective amount of nicotine or a muscarinic receptor antagonist.  
     
     
         46 . The method of  claim 39  wherein the bupropion metabolite, or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof, is adjunctively administered with a therapeutically effective amount of nicotine.  
     
     
         47 . The method of  claim 46  wherein the nicotine and/or bupropion metabolite or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof, is administered orally, mucosally, or transdermally.  
     
     
         48 . The method of  claim 46  wherein the nicotine and/or bupropion metabolite, or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof, is administered transdermally.  
     
     
         49 . A method of treating or preventing incontinence which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a bupropion metabolite, or a pharmaceutically acceptable salt, solvate, hydrate or clathrate thereof.  
     
     
         50 . The method of  claim 49  wherein the bupropion metabolite is optically pure.  
     
     
         51 . The method of  claim 49  wherein the optically pure bupropion metabolite is (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (R,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone; and (S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone.  
     
     
         52 . The method of  claim 51  wherein the optically pure bupropion metabolite is optically pure (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol.  
     
     
         53 . The method of  claim 49  wherein the incontinence is urinary incontinence.  
     
     
         54 . The method of  claim 53  wherein the urinary incontinence is stress urinary incontinence.  
     
     
         55 . The method of  claim 49  wherein the patient is a human of an age greater than about 50 years or less than about 13 years.  
     
     
         56 . A pharmaceutical composition which comprises a bupropion metabolite, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof, and a pharmaceutically acceptable diluent, carrier, or excipient.  
     
     
         57 . The pharmaceutical composition of  claim 56  wherein the bupropion metabolite is optically pure.  
     
     
         58 . The method of  claim 56  wherein the optically pure bupropion metabolite is (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (R,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone; or (S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone.  
     
     
         59 . The pharmaceutical composition of  claim 58  wherein the optically pure bupropion metabolite is optically pure (S,S)-hydroxybupropion.  
     
     
         60 . The pharmaceutical composition of  claim 56  wherein said pharmaceutical composition further comprises a second pharmacologically active compound selected from the group consisting of selective serotonin reuptake inhibitors, 5-HT 3  inhibitors, and nicotine.  
     
     
         61 . A pharmaceutical unit dosage form comprising a bupropion metabolite, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.  
     
     
         62 . The pharmaceutical unit dosage form of  claim 61  wherein said dosage form is stored in a sterile container.  
     
     
         63 . The pharmaceutical unit dosage form of  claim 61  wherein said dosage form is solid.  
     
     
         64 . The pharmaceutical unit dosage form of  claim 61  wherein said dosage form is a sterile solution or dispersion.  
     
     
         65 . The pharmaceutical unit dosage form of  claim 61  wherein said dosage form is a transdermal patch.  
     
     
         66 . The pharmaceutical unit dosage form of  claim 61  wherein the bupropion metabolite is optically pure.  
     
     
         67 . The pharmaceutical unit dosage form of  claim 62  wherein the optically pure bupropion metabolite is (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; (R,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (S,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol; (R)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone; or (S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone.  
     
     
         68 . The pharmaceutical unit dosage form of  claim 67  wherein the optically pure bupropion metabolite is optically pure (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5, 5-trimethyl-morpholinol.  
     
     
         69 . The pharmaceutical unit dosage form of  claim 61  wherein said dosage form further comprises a second pharmacologically active compound selected from the group consisting of selective serotonin reuptake inhibitors, 5-HT 3  inhibitors, and nicotine.  
     
     
         70 . The pharmaceutical unit dosage form of  claim 61  wherein said dosage form is suitable for oral, mucosal, or transdermal administration to a patient.  
     
     
         71 . A pharmaceutical unit dosage form suitable for transdermal administration to a patient which comprises nicotine and a bupropion metabolite or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.  
     
     
         72 . A lactose-free solid pharmaceutical unit dosage form comprising an a bupropion metabolite or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof and a non-lactose carrier, diluent, or excipient.  
     
     
         73 . The lactose-free solid pharmaceutical unit dosage form of  claim 72  wherein the bupropion metabolite is optically pure.  
     
     
         74 . The pharmaceutical unit dosage form of  claim 72  wherein said dosage form is an oral dosage form.  
     
     
         75 . A process for preparing optically pure (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof which comprises: 
 brominating 2-chloropropiophenone to form an intermediate;    contacting the intermediate with 2-amino-2-methyl-1-propanol under suitable reaction conditions for the formation of racemic 2-(3-chlorophenyl)-2-hydroxy-3,5, 5-trimethyl-morpholinol;    contacting the racemic 2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol with a chiral acid under suitable reaction conditions to form a mixture of diastereomeric salts;    isolating from the mixture of the diastereomeric salts a chiral salt of (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; and    contacting the chiral salt of (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5, 5-trimethyl-morpholinol with a base.    
     
     
         76 . The process of  claim 75  wherein the formation of diastereomeric salts and/or isolation of the chiral salt of (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5, 5-trimethyl-morpholinol gives a mother liquor.  
     
     
         77 . The process of  claim 75  wherein said mother liquor is contacted with a second chiral acid to form a second mixture of diastereomeric salts, from which the chiral salt of (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol is isolated.  
     
     
         78 . The process of  claim 77 , wherein the chiral acid is selected from the group consisting of optically pure derivatives of camphor, tartaric acid, malic acid, and mandelic acid.  
     
     
         79 . The process of  claim 75 , wherein the base is selected from the group consisting of potassium carbonate, potassium hydroxide, sodium hydroxide, and ammonium hydroxide.  
     
     
         80 . The process of  claim 75 , wherein the chiral acid is di-p-toluoyl-L-tartaric acid.  
     
     
         81 . A process for preparing racemic erythro-dihydrobupropion or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof which comprises: 
 reducing racemic bupropion with a suitable reducing agent to form a racemic erythro/threo dihydrobupropion mixture; and    isolating racemic erythro-dihydrobupropion from the mixture.    
     
     
         82 . The process of  claim 81  wherein the reducing agent is a metal hydride.  
     
     
         83 . The process of  claim 81  wherein the metal hydride is Red-Al.  
     
     
         84 . The process of  claim 81  wherein the acid is hydrobromic acid, hydroiodic acid, or hydrochloric acid.  
     
     
         85 . The process of  claim 84  wherein the acid is hydrochloric acid.  
     
     
         86 . A process for preparing optically pure erythro (R,S)-dihydrobupropion or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof which comprises: 
 contacting 3-chloropropiophenone with a silyl chloride under reaction conditions suitable for the formation of Z-1-(3-chlorophenyl-1-silyloxy)-1-propene intermediate;    asymmetrically dihydroxylating the intermediate under reaction conditions suitable for the formation of a 2-(S)-hydroxy intermediate;    converting the hydroxyl group of the 2-(S)-hydroxy intermediate to a leaving group and reacting with t-butyl amine; and    reducing the ketone.    
     
     
         87 . The process of  claim 86  wherein the base is selected from the group consisting of lithium diisopropylamide (LDA) and lithium hexamethyl disilylamide (LiHMDS).  
     
     
         88 . The process of  claim 86  wherein the silyl chloride is selected from the group consisting of trimethyl silyl chloride and tributyl silyl chloride.  
     
     
         89 . The process of  claim 86  wherein the silyl chloride is tert-butyldimethylsilyl chloride.  
     
     
         90 . The process of  claim 86  herein the leaving group is a tosylate, mesylate, or nosylate or a triflate.  
     
     
         91 . The process of  claim 90  wherein the leaving group is a triflate.  
     
     
         92 . The process of  claim 86  wherein the reducing agent is a metal hydride.  
     
     
         93 . The process of  claim 86  wherein the reducing agent is Red-Al.  
     
     
         94 . A process for preparing optically pure erythro (S,R)-dihydrobupropion or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof which comprises: 
 contacting 3-chloropropiophenone with a silyl halide under reaction conditions suitable for the formation of a Z-1-(3-chlorophenyl-1-silyloxy)-1-propene intermediate;    asymmetrically dihydroxylating the intermediate under reaction conditions suitable for the formation of a 2-(R)-hydroxy intermediate;    converting the hydroxyl group of the 2-(R)-hydroxy intermediate to a leaving group and reacting with t-butyl amine; and    reducing the ketone.    
     
     
         95 . The process of  claim 94  wherein the base is selected from the group consisting of lithium diusopropylamide (LDA) and lithium hexamethyl disilylamide (LiHMDS).  
     
     
         96 . The process of  claim 94  wherein the silyl halide is selected from the group consisting of trimethyl silyl chloride, tributyl silyl chloride, and tert-butyldimethylsilyl chloride.  
     
     
         97 . The process of  claim 94  wherein the leaving group is a tosylate, mesylate, or nosylate or a triflate.  
     
     
         98 . The process of  claim 94  wherein the leaving group is a triflate.  
     
     
         99 . The process of  claim 94  wherein the reducing agent is a metal hydride.  
     
     
         100 . The process of  claim 94  wherein the reducing agent is Red-Al.  
     
     
         101 . A process for preparing racemic-threo dihydrobupropion or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof which comprises: 
 reducing racemic bupropion to provide an product; and    purifying the product.    
     
     
         102 . The process of  claim 101  wherein the reducing agent is a metal hydride.  
     
     
         103 . The process of  claim 101  wherein the reducing agent is borane-tetrahydrofuran.  
     
     
         104 . A process for synthesizing racemic erythro-dihydro hydroxybupropion or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof which comprises 
 reducing racemic hydroxybupropion with a reducing agent; and    purifying racemic erythro-dihydro hydroxybupropion.    
     
     
         105 . The process of  claim 104  wherein the reducing agent is a metal hydride.  
     
     
         106 . The process of  claim 104  wherein the purification is chromatography, filtration, or crystallization.  
     
     
         107 . A process for synthesizing optically pure erythro (R,S)-dihydro hydroxybupropion or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof which comprises 
 reducing (S,S)-hydroxybupropion with a reducing agent; and    purifying to give optically pure erythro (R,S)-dihydro hydroxybupropion.    
     
     
         108 . The process of  claim 107  wherein the reducing agent is a metal hydride.  
     
     
         109 . The process of  claim 107  wherein the purification is chromatography, filtration, or crystallization.  
     
     
         110 . A process for synthesizing optically pure erythro (S,R)-dihydro hydroxybupropion or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof which comprises 
 reducing (R,R)-hydroxybupropion with a reducing agent; and    purifying to give optically pure erythro (S,R)-dihydro hydroxybupropion.    
     
     
         111 . The process of  claim 110  wherein the reducing agent is a metal hydride.  
     
     
         112 . The process of  claim 110  wherein the purification is chromatography, filtration, or crystallization.  
     
     
         113 . A process for synthesizing optically pure threo (S,S)-dihydro hydroxybupropion or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof which comprises 
 reducing (S,S)-hydroxybupropion with a reducing agent; and    purifying to give optically pure threo (S,S)-dihydro hydroxybupropion.    
     
     
         114 . The process of  claim 113  wherein the reducing agent is a metal hydride.  
     
     
         115 . The process of  claim 113  wherein the purification is chromatography, filtration, or crystallization.  
     
     
         116 . A process for synthesizing optically pure threo (R,R)-dihydro hydroxybupropion or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof which comprises 
 reducing (R,R)-hydroxybupropion with a reducing agent; and    purifying to give optically pure threo (R,R)-dihydro hydroxybupropion.    
     
     
         117 . The process of  claim 116  wherein the reducing agent is a metal hydride.  
     
     
         118 . The process of  claim 116  wherein the purification is chromatography, filtration, or crystallization.  
     
     
         119 . Optically pure (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5, 5-trimethyl-morpholinol hydrochloride.  
     
     
         120 . Optically pure (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5, 5-rimethyl-morpholinol hydrochloride.  
     
     
         121 . Optically pure (R,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol hydrochloride.  
     
     
         122 . Optically pure (S,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol hydrochloride.  
     
     
         123 . Optically pure (S,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol hydrochloride.  
     
     
         124 . Optically pure (R,S)-2-(Iert-butylamino)-1-(3-chlorophenyl)-propan-1-ol hydrochloride.  
     
     
         125 . Optically pure (R)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone hydrochloride.  
     
     
         126 . Optically pure (S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone hydrochloride.