Method for Producing (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclo-propylpropanoic Acid and the Crystalline Form Thereof for Use as a Pharmaceutical Ingredient

Abstract

The present invention relates to a novel and improved process for preparing (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of the formula (I), to the compound of the formula (I) in crystalline form and to their use for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular, cardiopulmonary and cardiorenal disorders.

Claims

1. A process for preparing (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3 cyclopropylpropanoic acid (I) in crystalline modification 1 (I-1), comprising stirring the compound of the formula (I) ##STR00128## in an inert solvent selected from the group consisting of heptane, 2-methoxy-2-methylpropane, ethanol, ethyl acetate and mixtures of these solvents at a temperature of from 20° C. to 120° C. and isolating the compound of the formula (I-1), optionally after cooling.

2. (canceled)

3. A process for preparing the compound of the formula (I), ##STR00129## comprising reacting the compound of the formula (V) ##STR00130## in which R.sup.1 represents (C.sub.1-C.sub.4)-alkyl, in the presence of dioxane and hydrochloric acid to give the compound of the formula (I).

4. A process for preparing the compound of the formula (V) ##STR00131## in which R.sup.1 represents (C.sub.1-C.sub.4)-alkyl, comprising reacting the compound of the formula (II) ##STR00132## under base-free conditions with the compound of the formula (III) ##STR00133## in which R.sup.1 represents (C.sub.1-C.sub.4)-alkyl.

5. A process for preparing the compound of the formula (II), ##STR00134## comprising converting the compound of the formula (XXVI) ##STR00135## in which R.sup.2 represents (C.sub.1-C.sub.4)-alkyl, with sodium methoxide in methanol and subsequent addition of water into the compounds of the formulae (II-Na) and (II-A-Na) ##STR00136## which precipitate as solids, adding a dilute mineral acid to convert the compounds of the formulae (II-Na) and (II-A-Na) into the compounds of the formulae (II) and (II-A) ##STR00137## reacting the compounds of the formulae (II) and (IIA) with a solution of quinine, resulting in the precipitation of the compound of the formula (II-Ch) ##STR00138## and adding dilute mineral acid to convert the compound of the formula (II-Ch) into the compound of the formula (II).

6. The process according to claim 5, further comprising purifying the compound of the formula (II-Ch) in a first step by crystallization from a mixture of water and methanol in a ratio of from 1:1 to 1:5 and in a second step by crystallization from a mixture of water and ethanol in a ratio of from 1:1 to 1:10.

7. A process for preparing the compound of the formula (XXVI) ##STR00139## in which R.sup.2 represents (C.sub.1-C.sub.4)-alkyl, comprising reacting the compound of the formula (XXIV) ##STR00140## in which R.sup.2 represents (C.sub.1-C.sub.4)-alkyl, with a lithium amide base and hydrolysing to give the compound of the formula (XXV) ##STR00141## in which R.sup.2 represents (C.sub.1-C.sub.4)-alkyl, wherein the hydrolysis is carried out by addition of an organic acid in an inert solvent and in a further step by addition of a mineral acid, and converting the compound of the formula (XXV) in a hydrogenation reaction into the compound of the formula (XXVI).

8. A process for preparing the compound of the formula (VII) ##STR00142## or a salt of this compound, comprising converting the compound of the formula (XXXIV) ##STR00143## in which R.sup.1 represents (C.sub.1-C.sub.4)-alkyl, with a base, a protic solvent, 1,5-cyclooctadiene, [Rh(COD)Cl].sub.2 and a compound of the formula (XXXV-A) or (XXXV-B) ##STR00144## in which R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 independently of one another represent hydrogen or (C.sub.1-C.sub.4)-alkyl, to the compound of the formula (III-rac) ##STR00145## in which R.sup.1 represents (C.sub.1-C.sub.4)-alkyl, conducting ester hydrolysis to give the compound of the formula (VII-rac), ##STR00146## reacting the compound of the formula (VII-rac) with a solution of (1S,2R)-(−)-cis-1-amino-2-indanol to give the compound of the formula (VII-I) ##STR00147## and adding dilute mineral acid to the compound of formula (VII-I) to form the compound of the formula (VII) or a salt thereof.

9. A process for preparing the compound of the formula (III) ##STR00148## in which R.sup.1 represents (C.sub.1-C.sub.4)-alkyl comprising converting the compound of the formula (XXXIV) ##STR00149## in which R.sup.1 represents (C.sub.1-C.sub.4)-alkyl, with exclusion of oxygen, with a suitable metal precursor, a suitable diene ligand, a suitable base and a compound of the formula (XXXV-A) or (XXXV-B) ##STR00150## in which R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 independently of one another represent hydrogen or (C.sub.1-C.sub.4)-alkyl into the compound of the formula (III).

10. (3S)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid in crystalline modification 1 (I-1) ##STR00151## characterized in that the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 7.0, 8.2, 11.1, 14.7, 17.2, 17.5, 18.7, 19.8.

11. (3S)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid in crystalline modification 1 (I-1) ##STR00152## characterized in that the IR spectrum of the compound exhibits band maxima at 1709, 1660, 1534, 1491, 1263, 1167, 1131, 1093, 1016 cm.sup.−1.

12. The process according to claim 3, wherein the compound of the formula V is prepared by reacting the compound of the formula (II) ##STR00153## under base-free conditions with the compound of the formula (III) ##STR00154## in which R.sup.1 represents (C.sub.1-C.sub.4)-alkyl.

Description

[0270] FIG. 1: X-ray diffractogram of the compound of the formula (I) in amorphous form

[0271] FIG. 2: X-ray diffractogram of the compound of the formula (I) in modification 1 (I-1)

[0272] FIG. 3: IR spectrum of the compound of the formula (I) in modification 1 (I-1)

[0273] The compounds according to the invention, the compound of the formula (I) and its compound of the formula (I) in crystalline form of modification 1 (I-1) act as activator of soluble guanylate cyclase and exhibit an unforeseeable, useful spectrum of pharmacological activity. They are therefore suitable for use as medicaments for treatment and/or prophylaxis of diseases in humans and animals.

[0274] In the context of the present invention, the term “treatment” or “treating” includes inhibition, retardation, checking, alleviating, attenuating, restricting, reducing, suppressing, repelling or healing of a disease, a condition, a disorder, an injury or a health problem, or the development, the course or the progression of such states and/or the symptoms of such states. The term “therapy” is understood here to be synonymous with the term “treatment”.

[0275] The terms “prevention”, “prophylaxis” and “preclusion” are used synonymously in the context of the present invention and refer to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disease, a condition, a disorder, an injury or a health problem, or a development or advancement of such states and/or the symptoms of such states.

[0276] The treatment or prevention of a disease, a condition, a disorder, an injury or a health problem may be partial or complete.

[0277] The compounds according to the invention are potent activators of soluble guanylate cyclase. They lead to vascular relaxation, inhibition of platelet aggregation and lowering of blood pressure, and they also increase coronary blood flow and microcirculation. These effects are mediated by a direct, haem-independent activation of soluble guanylate cyclase and an intracellular rise in cGMP.

[0278] The compounds according to the invention are especially suitable for treatment and/or prevention of cardiovascular, cardiopulmonary, cardiorenal, thromboembolic, fibrotic and pulmonary disorders.

[0279] Accordingly, the compounds of the invention can be used for treatment and/or prevention of cardiovascular and cardiopulmonary disorders, for example high blood pressure (hypertension), heart failure, coronary heart disorders and unstable angina pectoris, pulmonary arterial hypertension (PAH) and secondary forms of pulmonary hypertension (PH), renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, and conduction disorders, for example atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies), boxer cardiomyopathy, aneurysms, shock such as cardiogenic shock, septic shock and anaphylactic shock, and also for treatment and/or prevention of thromboembolic disorders and ischaemias such as myocardial ischaemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischaemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, oedema formation such as, for example, pulmonary oedema, cerebral oedema, renal oedema or oedema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), and also to prevent restenoses, for example after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA), heart transplants and bypass operations.

[0280] Owing to their activity profile, the compounds of the invention are also suitable for the prophylaxis and/or treatment of various disorders and disease-related states, in particular for the treatment and/or prophylaxis of primary and secondary forms of pulmonary hypertension, of acute pulmonary hypertension, in particular acute respiratory distress syndrome (ARDS), acute lung injury (ALI) and infant respiratory distress syndrome (IRDS), heart failure, angina pectoris, hypertension, thromboembolic disorders, ischaemias, vascular disorders, microcirculation impairments, renal insufficiency, fibrotic disorders and arteriosclerosis.

[0281] In the context of the present invention, the term “pulmonary hypertension” includes both primary and secondary sub-forms thereof as defined according to the Dana Point classification in accordance with their respective etiology (D. Montana and G. Simonneau et al.: A. J. Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3rd edition, Hodder Arnold Publ. 2011, pp. 197-206; Hoeper M. M. et al. 2009). These include in particular in group 1 pulmonary arterial hypertension (PAH), which, among others, embraces the idiopathic and the familial forms (IPAH and FPAH, respectively). Furthermore, PAH also embraces persistent pulmonary hypertension of the newborn and the associated pulmonary arterial hypertension (APAH) associated with collagenoses, congenital systemic pulmonary shunt lesions, portal hypertension, HIV infections, the intake of certain drugs and medicaments (for example of appetite suppressants), with disorders having a significant venous/capillary component such as pulmonary venoocclusive disorder and pulmonary capillary haemangiomatosis, or with other disorders such as disorders of the thyroid, glycogen storage diseases, Gaucher disease, hereditary teleangiectasia, haemoglobinopathies, myeloproliferative disorders and splenectomy. Group 2 of the Dana Point classification comprises PH patients having a causative left heart disorder, such as ventricular, atrial or valvular disorders. Group 3 comprises forms of pulmonary hypertension associated with a lung disorder, for example with chronic obstructive lung disease (COPD), interstitial lung disease (ILD), pulmonary fibrosis (IPF), and/or hypoxaemia (e.g. sleep apnoea syndrome, alveolar hypoventilation, chronic high-altitude sickness, hereditary deformities). Group 4 includes PH patients having chronic thrombotic and/or embolic disorders, for example in the case of thromboembolic obstruction of proximal and distal pulmonary arteries (CTEPH) or non-thrombotic embolisms (e.g. as a result of tumour disorders, parasites, foreign bodies). Less common forms of pulmonary hypertension, such as in patients suffering from sarcoidosis, histiocytosis X or lymphangiomatosis, are summarized in group 5.

[0282] In the context of the present invention, the term “heart failure” encompasses both acute and chronic forms of heart failure, and also specific or related disease types thereof, such as acute decompensated heart failure, right heart failure, left heart failure, global failure, ischaemic cardiomyopathy, dilatative cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid valve stenosis, tricuspid valve insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders and diastolic and systolic heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF).

[0283] In addition, the compounds according to the invention can also be used for treatment and/or prevention of arteriosclerosis, impaired lipid metabolism, hypolipoproteinaemias, dyslipidaemias, hypertriglyceridaemias, hyperlipidaemias, combined hyperlipidaemias, hypercholesterolaemias, abetalipoproteinaemia, sitosterolaemia, xanthomatosis, Tangier disease, adiposity, obesity and metabolic syndrome.

[0284] The compounds according to the invention can additionally be used for treatment and/or prevention of primary and secondary Raynaud's phenomenon, microcirculation impairments, claudication, hearing disorders, tinnitus, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic neuropathies, diabetic retinopathy, diabetic ulcers on the extremities, diabetic foot syndrome, gangrene, CREST syndrome, erythematosis, onychomycosis and rheumatic disorders.

[0285] In addition, the compounds according to the invention can be employed for the prevention of ischaemia- and/or reperfusion-related damage to organs or tissues and as additives for perfusion and preservation solutions for organs, organ parts, tissues or tissue parts of human or animal origin, in particular for surgical interventions or in the field of transplantation medicine.

[0286] The compounds of the invention are also suitable for treatment and/or prevention of renal disorders, in particular renal insufficiency and kidney failure. In the context of the present invention, the terms “renal insufficiency” and “kidney failure” encompass both acute and chronic manifestations thereof (chronic kidney disease; CKD) and also underlying or related renal disorders such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney disorders such as kidney transplant rejection and immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, diabetic kidney disease (DKD), proteinuric renal disorders, chronic renal insufficiency induced by acute renal failure, pyelonephritis, renal cysts, nephrosclerosis, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis and nephrotic syndrome which can be characterized diagnostically, for example by abnormally reduced creatinine and/or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium and/or creatinine, altered activity of renal enzymes, for example glutamyl synthetase, altered urine osmolarity or urine volume, elevated microalbuminuria, macroalbuminuria, lesions on glomerulae and arterioles, tubular dilatation, hyperphosphataemia and/or need for dialysis. The present invention also encompasses the use of the compounds of the invention for treatment and/or prevention of sequelae of renal insufficiency, for example hypertension, pulmonary oedema, heart failure, uraemia, anaemia, electrolyte disturbances (for example hyperkalaemia, hyponatraemia) and disturbances in carbohydrate metabolism.

[0287] In addition, the compounds of the invention are suitable for treatment and/or prevention of disorders of the urogenital system, for example benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), incontinence, for example mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence or overflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, and also erectile dysfunction and female sexual dysfunction.

[0288] The compounds of the invention are also suitable for treatment and/or prevention of asthmatic disorders, chronic obstructive pulmonary disorders (COPD), acute respiratory syndrome (ARDS) and acute lung damage (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), pulmonary emphysema (for example pulmonary emphysema induced by cigarette smoke) and cystic fibrosis (CF).

[0289] The compounds described in the present invention are also active compounds for control of central nervous system disorders characterized by disturbances of the NO/cGMP system. In particular, they are suitable for improving perception, concentration, learning or memory after cognitive impairments like those occurring in particular in association with situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory losses, vascular dementia, craniocerebral trauma, stroke, dementia occurring after strokes (post-stroke dementia), post-traumatic craniocerebral trauma, general concentration impairments, concentration impairments in children with learning and memory problems, Alzheimer's disease, Lewy body dementia, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis. They are also suitable for treatment and/or prevention of central nervous system disorders such as states of anxiety, tension and depression, CNS-related sexual dysfunctions and sleep disturbances, and for controlling pathological disturbances of the intake of food, stimulants and addictive substances.

[0290] In addition, the compounds of the invention are also suitable for controlling cerebral blood flow and are thus effective agents for controlling migraine. They are also suitable for the prophylaxis and control of sequelae of cerebral infarct (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma. The compounds of the invention can likewise be employed for controlling states of pain.

[0291] In addition, the compounds of the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for treatment and/or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammations (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin disorders and inflammatory eye disorders.

[0292] The compounds of the invention are also suitable for treatment and/or prevention of fibrotic disorders of the internal organs, for example the lung, the heart, the kidneys, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders. In the context of the present invention, the term “fibrotic disorders” includes in particular disorders such as hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, systemic sclerosis, morphea, keloids, hypertrophic scarring, naevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis). The compounds of the invention can likewise be used for promotion of wound healing, for controlling postoperative scarring, for example following glaucoma operations and cosmetically for ageing and keratinized skin.

[0293] Furthermore, the compounds of the invention are suitable for treatment and/or prevention of ophthalmological disorders which, for the purposes of the invention, should be understood to mean, for example, the following disorders: age-related macular degeneration (AMD) including dry (non-exudative) and wet (exudative, neovascular) AMD, choroidal neovascularization (CNV), choroidal neovascular membranes (CNVM), cystoid macular oedema (CME), epiretinal membranes (ERM) and macular perforations, myopia-associated choroidal neovascularization, angioid and vascular streaks, retinal detachment, diabetic retinopathy, diabetic macular oedema (DME), atrophic and hypertrophic lesions in the retinal pigment epithelium, retinal vein occlusion, choroidal retinal vein occlusion, macular oedema, macular oedema associated with retinal vein occlusion, Retinitis pigmentosa, Stargardt disease, retinopathy of prematurity, glaucoma, inflammation disorders of the eye, for example uveitis, scleritis or endocarditis, cataract, refraction anomalies, for example myopia, hyperopia, astigmatism or keratoconus, corneal angiogenesis resulting, for example, from keratitis, corneal transplant or keratoplasty, corneal angiogenesis resulting from hypoxia (for example through extensive wearing of contact lenses), conjunctival pterygium, subcorneal oedema and intracorneal oedema.

[0294] By virtue of their activity profile, the compounds of the invention are suitable in particular for the treatment and/or prevention of cardiovascular and cardiopulmonary disorders such as primary and secondary forms of pulmonary hypertension, heart failure, angina pectoris and hypertension and also of thromboembolic disorders, ischaemias, vascular disorders, impaired microcirculation, renal insufficiency, fibrotic disorders and arteriosclerosis.

[0295] The present invention further provides for the use of the compounds according to the invention for the treatment and/or prevention of disorders, especially of the aforementioned disorders.

[0296] The present invention further provides for the use of the compounds of the invention for production of a medicament for treatment and/or prevention of disorders, especially of the aforementioned disorders.

[0297] The present invention further provides a medicament comprising at least one of the compounds of the invention for treatment and/or prevention of disorders, especially of the aforementioned disorders.

[0298] The present invention further provides for the use of the compounds of the invention in a method for treatment and/or prevention of disorders, especially of the aforementioned disorders.

[0299] The present invention further provides a process for treatment and/or prevention of disorders, especially of the aforementioned disorders, using an effective amount of at least one of the compounds of the invention.

[0300] The present invention further provides a process for treatment and/or prevention of sickle cell anaemia, where traumatized patients receive a synthetic blood substitute, and for preservation of blood substitutes.

[0301] The present invention further provides for the use of the compounds according to the invention for treatment and/or prevention of disorders, especially of the aforementioned disorders, where a liquid aerosol is produced using an aerosol generator.

[0302] The present invention further provides for the use of the compounds according to the invention for treatment and/or prevention of disorders, especially of the aforementioned disorders, where the addition of β-cyclodextrin, selected from a list comprising unsubstituted β-cyclodextrin, methyl-O-cyclodextrin and (2-hydroxypropyl)-O-cyclodextrin, to the pharmaceutical formulation does not change systemic blood pressure.

[0303] The present invention further provides for the use of the compounds according to the invention for treatment and/or prevention of disorders, especially of the aforementioned disorders, where the addition of β-cyclodextrin, selected from a list comprising unsubstituted β-cyclodextrin, methyl-O-cyclodextrin and (2-hydroxypropyl)-β-cyclodextrin, to the pharmaceutical formulation does not change the pharmacokinetic profile of the compound of the formula (I).

[0304] The compounds according to the invention can be used alone or, if required, in combination with other active compounds. The present invention further provides medicaments comprising at least one of the compounds of the invention and one or more further active compounds, especially for the treatment and/or prophylaxis of the aforementioned disorders. Preferred examples of active compounds suitable for combinations include: [0305] organic nitrates and NO donors, for example sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO; [0306] compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP), for example inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and/or 5, especially PDE 4 inhibitors such as roflumilast or revamilast and PDE 5 inhibitors such as sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, mirodenafil or lodenafil; [0307] NO-independent but haem-dependent stimulators of guanylate cyclase, especially riociguat, nelociguat, vericiguat and those in WO 00/06568, WO 00/06569, WO 02/42301, WO 03/095451, WO 2011/147809, WO 2012/004258, WO 2012/028647 and WO 2012/059549; [0308] prostacyclin analogues and IP receptor agonists, by way of example and with preference iloprost, beraprost, treprostinil, epoprostenol, NS-304, selexipag or ralinepag; [0309] endothelin receptor antagonists, by way of example and with preference bosentan, darusentan, ambrisentan, macicentan or sitaxsentan; [0310] inhibitors of human neutrophil elastase (HNE), by way of example and with preference sivelestat or DX-890 (Reltran); [0311] compounds which inhibit the signal transduction cascade, in particular from the group of the tyrosine kinase inhibitors, by way of example and with preference dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib, masitinib or tandutinib; [0312] Rho kinase inhibitors, by way of example and with preference fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049; [0313] anti-obstructive agents as used, for example, for the therapy of chronic obstructive pulmonary disease (COPD) or bronchial asthma, by way of example and with preference, inhalatively or systemically administered beta-receptor mimetics (e.g. bedoradrine) or inhalatively administered anti-muscarinergic substances; [0314] anti-inflammatory and/or immunosuppressive agents as used, for example, for the therapy of chronic obstructive pulmonary disease (COPD), bronchial asthma or pulmonary fibrosis, such as, by way of example and with preference, systemically or inhalatively administered corticosteroids, flutiform, pirfenidone, acetylcysteine, azathioprine or BIBF-1120; [0315] chemotherapeutics like those employed, for example, for the therapy of neoplasms in the lung or other organs; [0316] active compounds used for the systemic and/or inhalative treatment of pulmonary disorders, for example for cystic fibrosis (alpha-1-antitrypsin, aztreonam, ivacaftor, lumacaftor, ataluren, amikacin, levofloxacin), chronic obstructive pulmonary disease (COPD) (LAS40464, PT003, SUN-101), acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) (interferon-beta-1a, traumakines), obstructive sleep apnoea (VI-0521), bronchiectasis (mannitol, ciprofloxacin), bronchiolitis obliterans (cyclosporin, aztreonam) and sepsis (pagibaximab, Voluven, ART-123); [0317] antithrombotic agents, by way of example and with preference from the group of the platelet aggregation inhibitors, the anticoagulants or the profibrinolytic substances; [0318] hypotensive active compounds, by way of example and with preference from the group of the calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, and the diuretics; and/or [0319] active compounds altering lipid metabolism, for example and with preference from the group of the thyroid receptor agonists, cholesterol synthesis inhibitors, by way of example and preferably HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein(a) antagonists; [0320] active compounds which inhibit neoangiogenesis, by way of example and with preference inhibitors of the VEGF and/or PDGF signalling pathways, inhibitors of the integrin signalling pathways, inhibitors of the angiopoietin-Tie signalling pathways, inhibitors of the PI3K-Akt-mTor signalling pathways, inhibitors of the Ras-Raf-Mek-Erk signalling pathway, inhibitors of the MAPK signalling pathways, inhibitors of the FGF signalling pathways, inhibitors of the sphingosine-1-phosphate signalling pathways, inhibitors of endothelial cell proliferation or apoptosis-inducing active ingredients; [0321] active compounds which reduce vascular wall permeability (oedema formation), by way of example and with preference corticosteroids, inhibitors of the ALK1-Smad1/5 signalling pathway, inhibitors of the VEGF and/or PDGF signalling pathways, cyclooxygenase inhibitors, inhibitors of the kallikrein-kinin system or inhibitors of the sphingosine-1-phosphate signalling pathways; and/or [0322] active compounds which reduce damage to the retina under oxidative stress, by way of example and with preference inhibitors of the complement system, especially antagonists of the complement C5a receptor, or agonists of the 5-HT.sub.1A receptor; [0323] antioxidants and free-radical scavengers; [0324] hypotensive active compounds, by way of example and with preference from the group of the calcium antagonists, angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers, diuretics, phosphodiesterase inhibitors, sGC stimulators, cGMP elevators, aldosterone antagonists, mineralocorticoid receptor antagonists, ECE inhibitors and vasopeptidase inhibitors; [0325] antidiabetics, by way of example and with preference from the group of the insulins and insulin derivatives, sulfonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors, PPAR-gamma agonists, GLP 1 receptor agonists, glucagon antagonists, insulin sensitizers, CCK1 receptor agonists, leptin receptor agonists, potassium channel antagonists and the inhibitors of hepatic enzymes that are involved in the stimulation of gluconeogenesis and/or glycogenolysis; [0326] anti-infectives, by way of example and with preference from the group of the antibacterial, antifungal and/or antiviral active substances; and/or [0327] substances for treatment of glaucoma, by way of example and with preference from the group of the adrenergics, beta-blockers, carbonic anhydrase inhibitors, parasympathomimetics and prostaglandins.

[0328] Antithrombotic agents are preferably understood to mean compounds from the group of the platelet aggregation inhibitors, the anticoagulants or the profibrinolytic substances.

[0329] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a platelet aggregation inhibitor, by way of example and with preference aspirin, clopidogrel, ticlopidine or dipyridamole.

[0330] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thrombin inhibitor, by way of example and with preference ximelagatran, melagatran, dabigatran, bivalirudin or clexane.

[0331] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a GPIIb/IIIa antagonist, by way of example and with preference tirofiban or abciximab.

[0332] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a factor Xa inhibitor, by way of example and with preference rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

[0333] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with heparin or with a low molecular weight (LMW) heparin derivative.

[0334] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a vitamin K antagonist, by way of example and with preference coumarin.

[0335] Hypotensive agents are preferably understood to mean compounds from the group of the calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, and the diuretics.

[0336] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a calcium antagonist, by way of example and with preference nifedipine, amlodipine, verapamil or diltiazem.

[0337] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an alpha-1 receptor blocker, by way of example and with preference prazosin.

[0338] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a beta receptor blocker, by way of example and with preference propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

[0339] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an angiotensin AII antagonist, by way of example and with preference losartan, candesartan, valsartan, telmisartan or embursatan.

[0340] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an ACE inhibitor, by way of example and with preference enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

[0341] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an endothelin antagonist, by way of example and with preference bosentan, darusentan, ambrisentan or sitaxsentan.

[0342] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor, by way of example and with preference aliskiren, SPP-600 or SPP-800.

[0343] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a mineralocorticoid receptor antagonist, by way of example and with preference spironolactone, eplerenone or finerenone.

[0344] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a diuretic, by way of example and with preference furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene. [0345] natriuretic peptides, for example atrial natriuretic peptide (ANP, anaritide), B-type natriuretic peptide or brain natriuretic peptide (BNP, nesiritide), C-type natriuretic peptide (CNP) and urodilatin; [0346] inhibitors of endopeptidases (NEP inhibitors) such as sacubitril, omapatrilate or AVE-7688, or in dual combination (‘ARNIs’) with angiotensin receptor blockers (e.g. valsartan), e.g. LCZ696.

[0347] Lipid metabolism modifiers are preferably understood to mean compounds from the group of the CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein(a) antagonists.

[0348] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a CETP inhibitor, by way of example and with preference torcetrapib (CP-5294/4), JJT-705 or CETP vaccine (Avant).

[0349] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist, by way of example and with preference D-thyroxine, 3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

[0350] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, by way of example and with preference lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

[0351] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a squalene synthesis inhibitor, by way of example and with preference BMS-188494 or TAK475.

[0352] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an ACAT inhibitor, by way of example and with preference avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

[0353] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an MTP inhibitor, by way of example and with preference implitapide, BMS-201038, R-103757 or JTT-130.

[0354] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-gamma agonist, by way of example and with preference pioglitazone or rosiglitazone.

[0355] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-delta agonist, by way of example and with preference GW 501516 or BAY 68-5042.

[0356] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a cholesterol absorption inhibitor, by way of example and with preference ezetimibe, tiqueside or pamaqueside.

[0357] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipase inhibitor, by way of example and with preference orlistat.

[0358] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorber, by way of example and with preference cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.

[0359] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a bile acid reabsorption inhibitor, by way of example and with preference ASBT (=IBAT) inhibitors, for example AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

[0360] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipoprotein(a) antagonist, by way of example and with preference gemcabene calcium (CI1027) or nicotinic acid.

[0361] The present invention further provides medicaments which comprise at least one compound of the invention, typically together with one or more inert, non-toxic, pharmaceutically suitable excipients, and for the use thereof for the aforementioned purposes.

[0362] The compounds according to the invention can act systemically and/or locally. For this purpose, they can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as an implant or stent.

[0363] The compounds according to the invention can be administered in administration forms suitable for these administration routes.

[0364] Suitable administration forms for oral administration are those which work according to the prior art and release the compounds of the invention rapidly and/or in a modified manner and which contain the compounds of the invention in crystalline and/or amorphized and/or dissolved form, for example tablets (uncoated or coated tablets, for example with gastric juice-resistant or retarded-dissolution or insoluble coatings which control the release of the compound of the invention), tablets or films/oblates which disintegrate rapidly in the oral cavity, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

[0365] Parenteral administration can be accomplished with avoidance of a resorption step (for example by an intravenous, intraarterial, intracardiac, intraspinal or intralumbar route) or with inclusion of a resorption (for example by an intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal route). Administration forms suitable for parenteral administration include inter alia preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

[0366] For the other administration routes, suitable examples are inhalable medicament forms (including powder inhalers, nebulizers), nasal drops, solutions or sprays, tablets, films/oblates or capsules for lingual, sublingual or buccal administration, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, sprinkling powders, implants or stents.

[0367] Oral and parenteral administration are preferred, especially oral and intravenous administration.

[0368] The compounds according to the invention can be converted to the administration forms mentioned. This can be accomplished in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include inter alia carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecylsulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants, for example ascorbic acid), colorants (e.g. inorganic pigments, for example iron oxides) and flavour and/or odour correctors.

[0369] In general, it has been found to be advantageous in the case of parenteral administration to administer amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg body weight to achieve effective results. In the case of oral administration the dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and most preferably 0.1 to 10 mg/kg body weight.

[0370] It may nevertheless be necessary in some cases to deviate from the stated amounts, and specifically as a function of body weight, route of administration, individual response to the active ingredient, nature of the preparation and time at which or interval over which administration takes place. Thus in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of administration of greater amounts, it may be advisable to divide them into several individual doses over the day.

[0371] The working examples which follow illustrate the invention. The invention is not restricted to the examples. Unless stated otherwise, the percentages in the tests and examples which follow are percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data for liquid/liquid solutions are based in each case on volume.

Experimental Section

Abbreviations and Acronyms

[0372] abs. absolute [0373] acac acetylacetonato [0374] BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) [0375] cat. catalytic [0376] CI chemical ionization (in MS) [0377] coe cyclooctene [0378] d day(s) [0379] TLC thin layer chromatography [0380] DCM dichloromethane [0381] DMA dimethylacetamide [0382] DMF dimethylformamide [0383] DMSO dimethyl sulfoxide [0384] ee enantiomeric excess [0385] EI electron impact ionization (in MS) [0386] ent enantiomer/enantiomerically pure [0387] eq equivalent(s) [0388] ESI electrospray ionization (in MS) [0389] EtOAc ethyl acetate [0390] GC-MS gas chromatography-coupled mass spectrometry [0391] % by weight percent by weight [0392] h hour(s) [0393] HPLC high-pressure, high-performance liquid chromatography [0394] ID internal diameter [0395] iPrOAc isopropyl acetate [0396] iPrOH isopropanol [0397] conc. concentrated [0398] LC-MS liquid chromatography-coupled mass spectrometry [0399] LDA lithium diisopropylamide [0400] LiHMDS lithium bis(trimethylsilyl)amide [0401] min minute(s) [0402] MS mass spectrometry [0403] MTBE 2-methoxy-2-methylpropane [0404] NMR nuclear magnetic resonance spectrometry [0405] NMP N-methyl-2-pyrrolidone [0406] Ph phenyl [0407] pTsOH p-toluenesulfonic acid [0408] Rf retention index (in TLC) [0409] RP-HPLC reversed phase high performance liquid chromatography [0410] RRT relative retention time [0411] R.sub.t retention time [0412] RT room temperature [0413] TESCl chlorotriethylsilane [0414] THF tetrahydrofuran [0415] v/v volume to volume ratio (of a solution) [0416] aq. aqueous, aqueous solution

[0417] HPLC, LC-MS and GC-MS methods:

[0418] Method A:

[0419] Instrument: Thermo Fisher-Scientific DSQ; chemical ionization; reactant gas NH3; source temperature: 200° C.; ionization energy 70 eV.

[0420] Method B:

[0421] Instrument: Micromass GCT, GC6890; column: Restek RTX-35, 15 m×200 μm×0.33 μm; constant helium flow rate: 0.88 ml/min; oven: 70° C.; inlet: 250° C.; gradient: 70° C., 30° C./min.fwdarw.310° C. (maintain for 3 min).

[0422] Method C:

[0423] Instrument: Thermo DFS, Trace GC Ultra; column: Restek RTX-35, 15 m×200 μm×0.33 μm; constant helium flow rate: 1.20 ml/min; oven: 60° C.; inlet: 220° C.; gradient: 60° C., 30° C./min.fwdarw.300° C. (maintain for 3.33 min).

[0424] Method D:

[0425] MS instrument type: Thermo Scientific FT-MS; instrument type UHPLC+: Thermo Scientific UltiMate 3000; column: Waters, HSST3, 2.1×75 mm, C18 1.8 μm; mobile phase A: 1 l of water+0.01% formic acid; mobile phase B: 11 of acetonitrile+0.01% formic acid; gradient: 0.0 min 10% B.fwdarw.2.5 min 95% B.fwdarw.3.5 min 95% B; oven: 50° C.; flow rate: 0.90 ml/min; UV detection: 210 nm/optimum integration path 210-300 nm.

[0426] Method E:

[0427] Instrument/detector high-performance liquid chromatograph with temperature-controlled column oven, UV detector and data evaluation system. Measurement wavelength: 226, bandwidth: 6 nm, column temperature 15° C., column: Chiralpak IA, length: 250 mm, internal diameter: 4.6 mm, particle size: 5 μm, mobile phase: A: 98% n-heptane+0.1% trifluoroacetic acid, B: 2% isopropanol+0.1% trifluoroacetic acid, flow rate: 1.0 ml/min, run time 20 min equilibration: 1 min, test solution about 2 mg/ml of the substance dissolved in isopropanol, injection volume 10 μl. Isomer 3 (main component): 14.39 min (RRT 1.00) isomer 1 (enantiomer): 12.35 min (RRT 0.86) isomer 2: 12.75 min (RRT 0.89), isomer 4: 16.13 min (RRT 1.12).

[0428] Method F:

[0429] Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; column: Restek RTX-35MS, 15 m×200 μm×0.33 μm; constant helium flow rate: 1.20 ml/min; oven: 60° C.; inlet: 220° C.; gradient: 60° C., 30° C./min.fwdarw.300° C. (maintain for 3.33 min).

[0430] Method G:

[0431] Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T31.8 μm 50×1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 11 of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 95% A.fwdarw.6.0 min 5% A.fwdarw.7.5 min 5% A; oven: 50° C.; flow rate: 0.35 ml/min; UV detection: 210-400 nm.

[0432] Method H:

[0433] Stationary phase: Zorbax SB-AQ (length 100 mm, ID 2.1 mm, particle size 1.8 μm); mobile phase A: 2 ml of 70% strength perchloric acid/1 l of water; mobile phase B: acetonitrile; UV detection at 210 nm; oven temperature: 45° C., injection volume: 1.5 μl; flow rate: 1.0 ml/min; linear gradient in 4 steps: 8% B.fwdarw.15% B (0.70 min), 15% B.fwdarw.42% B (0.30 min), 42% B.fwdarw.57% B (2.20 min), 57% B.fwdarw.100% B (1.80 min), 1.00 min isocratic at 100% B;

[0434] Method I:

[0435] Stationary phase: Chiralpak AD-H (length 250 mm, ID 4.6 mm, particle size 5 μm); mobile phase: 0.2 ml of trifluoroacetic acid/1 ml of water/100 ml of 2-propanol/900 ml of isohexane; UV detection at 220 nm; oven temperature: 30° C., injection volume: 5 μl; flow rate: 1.25 ml/min; isocratic (20 min);

Starting Materials and Intermediates

EXAMPLE 1

Methyl (4-chlorophenyl)acetate

[0436] ##STR00112##

[0437] At room temperature, 1000.0 g of 4-chlorophenylacetic acid were added to 10 ml of concentrated sulfuric acid (95-97%) in 2.41 of methanol, the solution was heated to 60° C. and stirred at this temperature for 2 h. The solution was cooled to room temperature and 200.0 g of sodium bicarbonate were added. 2050 ml of methanol were distilled off at 150 to 120 mbar, 2210 ml of toluene and 2100 ml of water were added to the residue and the phases were separated. The organic phase was washed with a solution of 50 g of sodium bicarbonate in 1000 ml of water, washed twice with in each case 600 ml of water and then concentrated to give an oil.

[0438] Yield: 1123.2 g (103.8% of theory). According to the NMR, the product contains about 3% toluene.

[0439] .sup.1H-NMR (400 MHz, CDCl.sub.3): 3.59 (s, 2H); 3.69 (s, 3H); 7.20-7.80 (m, 4H).

[0440] GC-MS (Method B) R.sub.t=4.06 min; 184.0 [M].sup.+.

EXAMPLE 2

Methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanoate (diastereomer mixture)

[0441] ##STR00113##

[0442] Method A:

[0443] 1489.5 ml (2.38 mol, 1.1 eq) of n-butyllithium (1.6 N) in hexane were cooled to −10° C. and 402.1 g (2.49 mol, 1.15 eq) of hexamethyldisilazane were added at −10 to −3° C. over 1.5 h. The resulting suspension was stirred at −6° C. for 10 min, 600 ml of tetrahydrofuran were added and the mixture was cooled to −72° C. Over 90 min, 400.0 g (2.17 mol) of methyl (4-chlorophenyl)acetate were added at at most −65° C. and the mixture was stirred at −78° C. for 0.5 h. A solution of 375.4 g (3.25 mol, 1.5 eq) of 1,1,1-trifluoroacetone in 400 ml of tetrahydrofuran was added over 2.5 h and the mixture was stirred for 10 min. 1000 ml (5 mol) of hydrochloric acid (5N) were then added over 5 min at at most 0° C. and the mixture was warmed to 22° C. and stirred for 0.5 h. The phases were separated and the organic phase was washed with 500 ml of water and concentrated under reduced pressure at 50° C. to give an oil.

[0444] Yield: 605.0 g (94.1% of theory)

[0445] The substance is present as a diastereomer mixture.

[0446] .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.02 (s, 1.9H); 1.55 (s, 1.1H); 1.60 (br. S, 0.4H), 3.60 (s, 0.3H); 3.72 (s, 3H); 3.78 (s, 0.7H); 3.94 (s, 0.3H) 5.48 (s, 0.6H) 7.30-7.40 (m, 4H).

[0447] GC-MS (Method C) R.sub.t=4.52 min, 296.0 [M].sup.+, 4.84 min, 296.0 [M].sup.+.

[0448] Method B:

[0449] In a stirred tank, 59.5 kg (0.140 kmol) of n-butyllithium (1.6 M in hexane) were cooled to 0° C., and 23.6 kg (0.146 kmol) of hexamethyldisilazane were metered in. Stirring was continued for 10 min and 21.4 kg of tetrahydrofuran were metered in. At −70° C., 24.0 kg (0.127 kmol) of methyl chlorophenylacetate were metered in and the reaction mixture was stirred for 3 h. A solution of 25.0 kg (0.218 kmol) of trifluoroacetone in 20.9 kg of tetrahydrofuran was then metered in at −70° C., the temperature of the reaction mixture was adjusted to −2° C. and 30.0 kg of water were metered in. At 10° C., 5.3 kg of ethyl acetate were added and the phases were separated. The organic phase was washed with 0.9 kg of sodium bicarbonate in 35.2 kg of water and then with 17.6 kg of water and 29.8 kg of hydrochloric acid (16.9% strength) and 14.7 kg of water. The organic phase was concentrated at 180 to 100 mbar and a jacket temperature of 40° to 50° C. and the oily product was withdrawn.

[0450] Yield: 30.6 kg, 84% pure based on the evaporation residue (68% of theory)

[0451] A sample was concentrated under reduced pressure and the evaporation residue was determined to be 84% pure.

[0452] MS (DCI) (Method A): 297.1 [M+H].sup.+; 314.1 [M+NH4].sup.+.

EXAMPLE 3

Methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbut-2-enoate (isomer mixture)

[0453] ##STR00114##

[0454] In a stirred tank, 151.3 kg of pyridine and 59.5 kg (0.170 kmol) of methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanoate were initially charged and volatile fractions were distilled off at 50 mbar until a bottom temperature of 38° C. had been reached. At 20° C., 39.1 kg (0.306 kmol) of phosphorus oxychloride were metered in. The mixture was heated to reflux temperature and stirred for a further 1.5 h. The mixture was cooled to 80° C. and 112 kg of water were metered in (highly exothermic). At 20° C., 151.4 kg of ethyl acetate were added and the separated organic phase was washed with 38.9 kg of hydrochloric acid (3.6% strength) and 38.2 kg of water and concentrated at 60 to 30 mbar and a jacket temperature of 45° C. to 55° C. 26.7 kg of tetrahydrofuran were added to the residue and the solution was withdrawn.

[0455] Yield: 37.5 kg of solution, yield about 79% of theory

[0456] The product consists of an isomer mixture.

[0457] GC MS (Method B) R.sub.t=3.93 min, 278.1 [M].sup.+; 3.97 min, 278.1 [M].sup.+; 4.12 min, 278.1 [M].sup.+;

EXAMPLE 4

Methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbut-3-enoate (diastereomer mixture)

[0458] ##STR00115##

[0459] In a stirred tank, 57.8 kg (0.136 kmol) of n-butyllithium (1.6 M in hexane) were cooled to 0° C., and 51.1 kg of tetrahydrofuran were added. 15.3 kg (0.150 kmol) of diisopropylamine were metered in and the mixture was cooled to −75° C. At this temperature, a solution of 18.9 kg (0.068 kmol) of methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbut-2-enoate (isomer mixture) in 19 kg of tetrahydrofuran was metered in and the reaction mixture was stirred for 1 h. A solution of 16.3 kg (0.272 kmol) of acetic acid in 32.6 kg of tetrahydrofuran was then metered in. At 10° C., 72.5 kg of water and 65.3 kg of ethyl acetate were added, 54.8 kg of hydrochloric acid (18% strength) were metered in and the phases were separated. The organic phase was concentrated at 30 mbar and a jacket temperature of 60° C. The residue (18.4 kg) was diluted with 3.7 kg of polyethylene glycol 400 and the product was distilled on a thin-film evaporator at a jacket temperature of 145° C./1 to 10 mbar.

[0460] Yield: 13.6 kg (72% of theory)

[0461] GC-MS (Method B) R.sub.t=3.98 min, 278.1 [M].sup.+.

EXAMPLE 5

Methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture)

[0462] ##STR00116##

[0463] 0.5 kg of catalyst (5% platinum on carbon, 50% water-wet) was added to a solution of 7.3 kg (0.026 kmol) of methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbut-3-enoate (XXIII) in 7.0 kg of methanol, and the mixture was hydrogenated at 50° C./80 bar. The catalyst was filtered off and the solution was withdrawn.

[0464] GC MS (Method B) R.sub.t=4.00 min, 280.1 [M].sup.+; 4.03 min, 280.1 [M].sup.+.

EXAMPLE 6

rel-(2R,3S)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid (enantiomer mixture)

[0465] ##STR00117##

[0466] At 20° C., 22.9 kg (0.127 kmol) of 30% sodium methoxide in methanol were metered into a solution of 19.8 kg (0.071 kmol) of methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoate in 36.3 kg of methanol and the mixture was stirred for 1.5 h. 118.7 kg of water were then metered in, the mixture was stirred for 0.5 h and low-boilers were distilled off up to a bottom temperature of 97° C. During the distillation, 29.7 kg of water were metered in. The mixture was cooled to 5° C. and the precipitated solid was isolated and washed with 16 kg of cold water. The moist product was suspended in 91.3 kg of water, 13.1 kg of hydrochloric acid (20% strength) were metered in at 20° C. and the suspension was stirred for 2 h. The solid was isolated, washed with 38.8 kg of water and dried under reduced pressure at a jacket temperature of 50° C. using nitrogen carrier gas.

[0467] Yield: 10.1 kg (53.5% of theory)

[0468] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 0.78 (d, 3H); 0.89 (m, 2H); 3.14-3.39 (m, 1H); 3.68 (m, 1H); 7.29-7.55 (m, 4H); 12.82 (br. s, 1H).

[0469] LC-MS (Method D) R.sub.1=1.85 min, 265.0243 [M−H].sup.−.

EXAMPLE 7

(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid—quinine salt

[0470] ##STR00118##

[0471] At reflux temperature, a solution of 19.3 kg (0.072 kmol) of rel-(2R,3S)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid in 92.5 kg of ethanol was metered into 17.6 kg (0.054 kmol) of quinine in 173.8 kg of ethanol and the mixture was stirred for 10 min. Over a period of 2.5 h, the mixture was cooled to 0° C. and stirred at this temperature for 1 h and the solid was isolated and washed with 69 kg of ethanol and 33.3 kg of water. The filter cake was then heated to reflux temperature in 236.3 kg of water and 630.9 kg of methanol and stirred for 0.5 h. The mixture was then cooled to 0° C. over a period of 5 h and stirred for 1 h and the solid was isolated and washed with a solution of 20.3 kg of methanol and 7.6 kg of water and then with 33.3 kg of water. The filter cake was then heated to reflux temperature in 98.3 kg of water and 481.4 kg of ethanol and stirred for 0.5 h. The mixture was then cooled to 0° C. over a period of 5 h and stirred for 1 h and the solid was isolated and washed with a solution of 21 kg of methanol and 6.6 kg of water and then with 33.3 kg of water and dried under reduced pressure (30 mbar) at a jacket temperature of 50° C. using nitrogen carrier gas.

[0472] Yield: 15.5 kg (35.3% of theory)

[0473] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 0.77 (d, 3H); 1.50-1.84 (m, 5H); 2.21-2.37 (m, 1H); 2.54-2.74 (m, 1H); 2.96-3.08 (m, 1H); 3.08-3.42 (m, 13H incl. H.sub.2O); 3.62 (d, 1H); 3.88 (s, 3H); 4.87-5.06 (m, 2H); 5.31-5.43 (m, 1H); 5.79-5.94 (m, 1H); 5.77 (br. s,1H); 7.33-7.44 (m, 5H); 7.46-7.56 (m, 2H); 7.93 (d, 1H); 8.69 (d, 1H).

[0474] LC-MS (Method D) R.sub.t=0.80 min 325.1 [M+H].sup.+ (quinine); 1.85 min 531.0 [2M−H].sup.− 265.0 [M−H].sup.− 221.0 [M−CO.sub.2—H].sup.− (2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid).

[0475] HPLC (Method E): 99.5% ee

EXAMPLE 8

(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid

[0476] ##STR00119##

[0477] At 20° C., 27.8 kg (0.190 kmol) of hydrochloric acid (25% strength) were metered into 32.1 kg (0.053 kmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid—quinine salt (1:1) in 268 kg of water and the mixture was stirred for 2.5 h. The solid was isolated and washed with 82.5 kg of water and dried under reduced pressure (30 mbar) at a jacket temperature of 50° C. using nitrogen carrier gas.

[0478] Yield: 14.4 kg (100% of theory)

[0479] HPLC (Method E): 99.1% ee

[0480] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.78 (d, 3H) 3.11-3.38 (m, 1H); 3.68 (d, 1H); 7.29-7.54 (m, 4H); 12.83 (br s, 1H).

[0481] LC-MS (Method D) R.sub.1=1.85 min 265.0 [M−H].sup.−.

EXAMPLE 9

tert-Butyl (2E)-3-cyclopropylprop-2-enoate

[0482] ##STR00120##

[0483] KOtBu (384 g, 3.42 mol) was suspended in 41 of toluene, and tert-butyl (diethoxyphosphoryl)acetate (864 g, 3.42 mol) was added at 15° C. to 30° C. After 1 h, the mixture was cooled to 0° C. and dissolved in cyclopropanecarbaldehyde (200 g, 2.85 mol) dissolved in 800 ml of toluene. The mixture was stirred for another 2 h and 51 of NH.sub.4Cl solution (20%) were then added. The organic phase was separated off, washed with 41 of NaCl solution (20%) and concentrated. The precipitated solid was filtered off, washed with a small amount of cold toluene and dried under reduced pressure, giving 286 g of a solid (yield 60% of theory).

[0484] GC MS (Method F) R.sub.t=1.21 min, M.sup.+=168.1;

[0485] .sup.1H-NMR (500 MHz, d6-DMSO): 0.63 (m, 2H); 0.89 (m, 2H); 1.41 (s, 9H); 1.60 (m, 1H); 5.82 (d, 1H); 6.28 (dd, 1H).

EXAMPLE 10

tert-Butyl 3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate 4-methylbenzenesulfonate

[0486] ##STR00121##

[0487] (+,−)-BINAP (29 g, 0.00575 eq) and [Rh(COD)Cl].sub.2 (9.8 g, 0.0025 eq) in 11 of THF were stirred exposed to the air for 15 min. In another vessel, 1.33 kg of tert-butyl (2E)-3-cyclopropylprop-2-enoate (7.92 mol), 630 g of KOH (9.51 mol), 2.21 kg of pinacol 3-amino-4-chlorophenylboronate (8.72 mol) and 9.7 ml of 1,5-cyclooctadiene (0.01 eq) were suspended under nitrogen in a mixture of 9.31 of THF and 730 ml of iPrOH. This mixture was heated to 60° C. and the catalyst mixture was added. The mixture was stirred at this temperature for a further 9 h. The reaction mixture was cooled to 0° C. and 8 l of water were added. The phases were separated and the aqueous phase was extracted with 2.71 of EtOAc. The combined organic phases were washed with 2.71 of concentrated NaCl solution. This solution was returned to the vessel and 2.11 kg (11.1 mol) of pTsOH were added a little at a time at 15° C. to 20° C. After 1 h, the suspension was filtered and the product was washed with EtOAc and dried under reduced pressure, giving 3.4 kg (93% of theory) of a solid.

[0488] .sup.1H-NMR (500 MHz, d6-DMSO): 0.07 (m, 1H); 0.21 (m, 1H); 0.32 (m, 1H); 0.50 (m, 1H); 0.93 (m, 1H); 1.28 (s, 9H); 2.11 (m, 1H); 2.29 (s, 3H); 2.49 (dd, 1H); 2.59 (dd, 1H); 6.54 (d, 1H); 6.73 (d, 1H); 7.12 (m, 3H); 7.47 (d, 2H).

EXAMPLE 11

3-(3-Amino-4-chlorophenyl)-3-cyclopropylpropanoic acid

[0489] ##STR00122##

[0490] At 22° C., 1.90 kg of tert-butyl 3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate 4-methylbenzenesulfonate and 154 g of pTsOH (0.2 eq) were suspended in 3.81 of HOAc. The suspension was heated to 60° C. and stirred for 1 h. The reaction mixture was cooled to 0° C., 8.6 l of water were added and the pH was adjusted to pH=12 using 6.5 kg of concentrated aqueous sodium hydroxide solution (45%) NaOH. The aqueous phase was extracted twice with iPrOAc (3.81 and 0.81). Concentrated aqueous hydrochloric acid (32% strength) was added to the aqueous solution, and 3.51 of DCM were added. The phases were separated and the organic phase was washed with 0.8 l of water. The crude solution was used for the subsequent crystallization.

[0491] For crystallization, three crude solutions were combined. The DCM was removed under reduced pressure and 2.91 of methylcyclohexane were added. The suspension was concentrated and 2.91 of methylcyclohexane were added. This operation was repeated, with removal of methylcyclohexane under reduced pressure and addition of a further 2.91. After the last addition of methylcyclohexane, the methylcyclohexane was removed under reduced pressure and 0.61 of DCM and 0.61 of methylcyclohexane were added. At 45° C., the solution was seeded with 2 g of crystalline product. The suspension was cooled to 0° C., washed with methylcyclohexane and dried under reduced pressure, giving 2.23 kg (78% of theory) of a solid.

[0492] .sup.1H-NMR (500 MHz, d6-DMSO): 0.07 (m, 1H); 0.21 (m, 1H); 0.31 (m, 1H); 0.48 (m, 1H); 0.92 (m, 1H); 2.11 (m, 1H); 2.55 (dd, 1H); 2.61 (dd, 1H); 6.44 (dd, 1H); 6.65 (d, 1H); 7.06 (d, 1H).

EXAMPLE 12

(3S)-3-(3-Amino-4-chlorophenyl)-3-cyclopropylpropanoic acid (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol

[0493] ##STR00123##

[0494] 1.40 kg of 3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoic acid were suspended in 15.5 kg of acetonitrile and 1 l of water. The mixture was heated to 60° C. and 0.7 kg of (1S,2R)-(−)-cis-1-amino-2-indanol was added. The reaction mixture was seeded and, over 5 h, slowly cooled to 22° C. The product was filtered off, suspended in 12 kg of acetonitrile and 0.8 l of water and heated to 75° C. More acetonitrile and water 3.81 (9.5:0.5; ACN:water) were added until a clear solution had formed. The solution was seeded with crystalline product and the suspension was, over 6 h, cooled to 22° C. The suspension was cooled to 0° C., stirred for 1 h, filtered and washed with acetonitrile. The indanol salt formed was dried under reduced pressure, giving 880 g (39% of theory) of a solid.

[0495] HPLC MS (Method G) R.sub.t=0.84 min, MH.sup.+=240.1;

[0496] .sup.1H-NMR (500 MHz, d6-DMSO): 0.06 (m, 1H); 0.21 (m, 1H); 0.30 (m, 1H); 0.47 (m, 1H); 0.90 (m, 1H); 2.15 (q, 1H); 2.48 (m, 2H); 2.78 (d, 1H); 2.96 (dd, 1H); 4.12 (s, 1H); 4.28 (s, 1H); 6.45 (dd, 1H); 6.66 (d, 1H); 7.05 (d, 1H); 7.18 (m, 3H); 7.34 (m, 1H).

EXAMPLE 13

(3S)-3-(3-Amino-4-chlorophenyl)-3-cyclopropylpropanoic acid hydrochloride

[0497] ##STR00124##

[0498] For salt resolution, several batches of the indanol salt were combined. 1.35 kg of (3S)-3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoic acid indanol salt were suspended in 13.51 of EtOAc and 6.75 l of water, and 610 ml of HCl (16% in water) were added. The phases were separated and the organic phase was washed twice with water (2×3.4 l of water), dried with sodium sulfate and concentrated, giving 860 g (100% of theory) of an oily product.

[0499] The free amino acid 860 g was dissolved in 1.91 of EtOAc, and 900 ml of HCl in dioxane (4 M) were added. The product was filtered off, washed with EtOAc and dried, giving 936 g (94% of theory) of a solid having an enantiomeric purity of 99.4%.

[0500] HPLC MS (Method G) R.sub.t=0.84 min, MH.sup.+=240.1;

[0501] .sup.1H-NMR (500 MHz, d6-DMSO): 0.09 (m, 1H); 0.23 (m, 1H); 0.32 (m, 1H); 0.50 (m, 1H); 0.93 (m, 1H); 2.16 (q, 1H); 2.55 (dd, 1H); 2.63 (dd, 1H); 6.64 (m, 1H); 6.84 (m, 1H); 7.17 (m, 1H).

EXAMPLE 14

(3S)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid

[0502] ##STR00125##

[0503] Method A:

[0504] (2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid (1.43 kg) was suspended in 6.6 kg of THF, and 28 g of DMF were added. At 20° C., oxalyl chloride (680 g) was added and stirring was continued for 45 min.

[0505] In another vessel, (3S)-3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoic acid hydrochloride (1:1) (1.48 kg) was suspended in 6.6 kg of THF, and 3.45 kg of diisopropylethylamine were added at 20° C. At this temperature, TESCl (1.05 kg) was added, and stirring was continued for 1 h.

[0506] At 0° C., the TES-protected amino acid was added slowly to the acid chloride, and the empty vessel was washed with 1 kg of THF. After 1.5 h of stirring, EtOAc (6.2 kg) and 2 N HCl (7.4 kg) were added, and the phases were separated. The organic phase was washed with a further 7.4 kg of 2 N HCl solution and washed twice with 7.4 kg of 10% strength NaCl solution in water. The solution was filtered and washed with EtOAc. The EtOAc was removed under reduced pressure, and 13.6 kg of heptane were added. The distillation was continued, and a further 5.5 kg of heptane were added. The reaction mixture was seeded at 55° C. and slowly cooled to 0° C. The product was filtered off, washed with heptane and dried under reduced pressure, giving 1.72 kg (67% of theory) of the desired product as a solid.

[0507] .sup.1H-NMR (500 MHz, d6-DMSO): 0.07 (m, 1H); 0.23 (m, 1H); 0.28 (m, 1H); 0.49 (m, 1H); 0.80 (d, 3H); 0.94 (m, 1H); 2.24 (m, 1H); 2.56 (dd, 1H); 2.64 (dd, 1H); 3.37 (m, 1H); 4.13 (d, 1H); 7.10 (dd, 1H); 7.36 (d, 1H); 7.41 (d, 1H); 7.46 (m, 4H); 9.83 (s, 1H); 12.04 (s, 1H).

[0508] Method B:

[0509] tert-Butyl (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoate (160 g) was dissolved in 2.2 kg of dioxane, and 670 g of HCl (32% in water) were added. The reaction mixture was heated to 50° C. and stirred for 12 h. After cooling to RT, 349 g of heptane and 844 g of water were added and the phases were separated. The aqueous phase was extracted with a mixture of 228 g of heptane and 495 g of MTBE. The organic phases were combined, washed with 1.3 kg of water and dried with sodium sulfate. Two of these batches were combined and the solvent was evaporated. At 40° C., the crude product was dissolved in 220 g of MTBE and 96 g of heptane. At 50° C., this solution was added slowly to 3897 g of heptane. The mixture was seeded with 1.5 g of product and slowly cooled to 0° C. The product was filtered off, washed with heptane and dried under reduced pressure, giving 250 g (88% of theory) as a solid.

[0510] .sup.1H-NMR (500 MHz, d6-DMSO): 0.07 (m, 1H); 0.23 (m, 1H); 0.28 (m, 1H); 0.49 (m, 1H); 0.80 (d, 3H); 0.94 (m, 1H); 2.24 (m, 1H); 2.56 (dd, 1H); 2.64 (dd, 1H); 3.37 (m, 1H); 4.13 (d, 1H); 7.10 (dd, 1H); 7.36 (d, 1H); 7.41 (d, 1H); 7.46 (m, 4H); 9.83 (s, 1H); 12.04 (s, 1H).

EXAMPLE 15

teat-Butyl (3S)-3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate

[0511] ##STR00126##

[0512] Under an atmosphere of nitrogen, 806 mg of (1S,4S)-2,5-diphenylbicyclo[2.2.2]octa-2,5-diene (3.12 mmol, 0.011 eq) and 1.16 g of [Rh(CH.sub.2═CH.sub.2).sub.2Cl].sub.2 (2.97 mmol, 0.01 eq) were stirred in 35 ml of MeOH for 30 min.

[0513] In another flask, under an atmosphere of nitrogen, 50 g (297 mmol) of tert-butyl (2E)-3-cyclopropylprop-2-enoate, 82.9 g (327 mmol) of pinacol (3-amino-4-chlorophenyl)boronate and 1.67 g of KOH (29.7 mmol) were suspended in MeOH (350 ml) and water (35 ml) and heated to 50° C. The catalyst solution was added and stirring was continued for 17 h. Water and EtOAc (150 ml) were added and the phases were separated. 73.5 g of pTsOH (386 mmol) were added to the organic phase and the solid formed was isolated, washed with EtOAc and dried under reduced pressure, giving 107 g (77% of theory) with an enantiomeric excess of 97.1%.

EXAMPLE 16

tert-Butyl (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoate

[0514] ##STR00127##

[0515] (2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid (104 g, 389 mmol) was suspended in 11 of THF, and 2 ml of DMF were added. At 20° C., oxalyl chloride (54 g, 428 mmol) was added and stirring was continued for 45 min.

[0516] In another vessel, tert-butyl (3S)-3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate (115 g, 389 mmol) was dissolved in 11 of THF, and 114 m (3.89 mol) of pyridine were added at 20° C. At this temperature, the acid chloride was added slowly, and stirring was continued for 1 h. The reaction was quenched by addition of 800 ml of 20% strength citric acid, and the phases were separated. The organic phase was further washed with 800 ml of 20% strength citric acid and water (2×800 ml). The solvent was evaporated and the residue was dissolved in 160 ml of MTBE and 650 ml of heptane. The reaction mixture was concentrated to half its original volume and slowly cooled to RT. The product was filtered off, washed with heptane and dried under reduced pressure, giving 183 g (86% of theory) of a solid.

[0517] .sup.1H-NMR (500 MHz, d6-DMSO): 0.07 (m, 1H); 0.22 (m, 1H); 0.30 (m, 1H); 0.50 (m, 1H); 0.80 (d, 3H); 0.94 (m, 1H); 2.20 (m, 1H); 2.52 (dd, 1H); 2.62 (dd, 1H); 3.36 (m, 1H); 4.13 (d, 1H); 7.11 (dd, 1H); 7.36 (d, 1H); 7.43 (d, 1H); 7.46 (m, 4H); 9.80 (s, 1H)