HK1070644A - Process for the preparation of the mesylate salt trihydrate of 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol - Google Patents

Description

Method for preparing mesylate salt trihydrate of 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol

The application is a divisional application of Chinese patent application with the application number of 01117171.5, the application date of 2001, 4 months and 27 days, and the invention name of "a preparation method of mesylate trihydrate of 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol".

The present invention relates to a process for the preparation of the mesylate trihydrate of the compound (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol of formula (I) from its D- (-) -tartrate salt:

the compound of formula (I) (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol exhibits potent activity as an NMDA (N-methyl-D-aspartate) receptor antagonist and is useful in the treatment of epilepsy, anxiety, cerebral ischemia, muscle spasms, multi-infarct dementia, traumatic brain injury, pain, AIDS-related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal syndrome, psychiatric disorders, urinary incontinence and degenerative CNS (central nervous system) disorders such as stroke, alzheimer ' S disease, parkinson ' S disease and huntington ' S chorea.

The mesylate salt trihydrate form of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol is useful as an active therapeutic agent because it has superior properties over the anhydrous mesylate salt. The mesylate trihydrate salt has a more stable crystalline form than the anhydrous mesylate salt and, therefore, has a substantially longer shelf life. In addition the trihydrate is not easily destroyed in the crystalline structure due to the inclusion of water in the crystals. U.S. Pat. No. 6008233 discloses a mesylate trihydrate, anhydrous mesylate and free base of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol, and methods for their preparation.

Furthermore, the free base, the inorganic methanesulfonate salt, and the method for its preparation are also fully disclosed in U.S. Pat. No. 5,5185343, issued 2.9.1993. Its use in the treatment of certain of the above-mentioned diseases is disclosed in particular in U.S. Pat. No. 5,5272160, granted on 12/21/1993; and international patent application PCT/IB 95/00380, which designates the united states, filed on month 5, 18, 1995 and published as WO 96/06081. Its combined use with a compound capable of increasing and thereby restoring the balance of excitatory feedback from the ventral nucleus of the thalamus into the cortex to treat parkinson's disease is disclosed in international patent application PCT/IB 95/00398, assigned to the united states, filed on 26.5.1995 and published as WO 96/37226. The above U.S. patents and patent applications are incorporated herein by reference in their entirety.

Summary of The Invention

The invention relates to a preparation method of a mesylate trihydrate of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol, which comprises the following steps:

the method comprises the following steps:

(i) dissolving the D- (-) -tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol in an aqueous methanesulfonic acid solution; and

(ii) the mesylate trihydrate is isolated from the solution.

In the above process, the molar ratio of methanesulfonic acid to the D- (-) tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol is preferably 1.3 to 1.0. More preferably the molar ratio of methanesulfonic acid to the D- (-) -tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol is between 1.10 and 1.05; most preferably between 1.10 and 1.08.

In the process of the present invention, the aqueous methanesulfonic acid solution of step (i) is suitably prepared using pyrogen-free water.

The present invention also relates to any of the above processes for the preparation of the mesylate salt trihydrate of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol, further comprising the steps of:

(i) mixing a racemic mixture containing compounds of formula (I) and (II)

Dissolving in aqueous methanol in the presence of D- (-) -tartaric acid; and

(ii) the D- (-) tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol was isolated from the solution. In this process, the aqueous methanol suitably has a water content of 5-20%. A more preferred embodiment is one wherein the aqueous methanol has a water content of 7-10%. The invention also relates to the work-up step for the enantiomeric resolution and separation of the (D) - (-) -tartrate salt of the compound of formula (I).

The present invention also relates to the D- (-) -tartrate salt of the compound of formula (I) (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol:

wherein the ratio of the (1S, 2S) -enantiomer to the (1R, 2R) -enantiomer is greater than 97%. More preferably, the ratio of the (1S, 2S) -enantiomer to the (1R, 2R) -enantiomer is greater than 98%.

Detailed Description

The mesylate salt trihydrate of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol is a white crystalline solid with a single crystal form and good solubility in water (solubility in aqueous buffer solutions at pH 3 and 7 of 25 and 15mg/ml, respectively). It is known that the equilibrium formation of the mesylate trihydrate occurs when the anhydrous mesylate salt is present in an environment having a relative humidity of 81%. Early preparation of the mesylate trihydrate, as described in US patent No. US6003233, required the use of the free base as starting material, which required an additional step in the overall synthesis of the free base compound of formula (I) following enantiomeric resolution, isolation and drying.

However, the present invention enables the preparation of mesylate trihydrate directly from the D- (-) -tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol without the need for a free base. The D- (-) -tartrate salt used in the above-mentioned method is the product of enantiomeric resolution of racemic (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) 1-propanol. Thus, the present invention provides a more efficient and less step process for the synthesis of the mesylate salt.

The process of the present invention further comprises an improved resolution process of the D- (-) -tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol. Previous methods for resolving (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol racemates, such as US6003233, involved selective crystallization from anhydrous methanol with an optically active tartrate salt and almost all followed by reslurrying (crystallization) of the slurry and/or recrystallization to obtain an acceptable enantiomeric purity of (1S, 2S) of 97% or better. Thus, the present invention provides a more efficient way of omitting repeated purification steps and in the overall synthetic route.

The following reaction scheme illustrates the process of the present invention.

Route 1

See scheme 1, racemic benzyl-protected ketone compounds of formula (III) are subjected to reducing conditions, or are treated with NaBH₄Mixtures of threo and erythro isomers are obtained in ethanol at 40-50 ℃ for 6-7 hours or with potassium selecteide (CalSelect K) in tetrahydrofuran at 10-20 ℃ for 1-2 hours, or any other moisture reagents and conditions known to those skilled in the art, wherein the threo isomer predominates in the crude reaction mixture in a ratio of about 80: 20 or better. The ethanol or THF solvent should not contain appreciable amounts of moisture, i.e., no more than 0.2-0.5% moisture. After actual separation from the solvent, a nearly 90% threo-oriented product can be obtained, i.e. a racemic mixture of threo components of the compound of formula (IVA)Mixtures (i.e. IVA-1 and IVA-2). The starting material of formula (III) is obtained by the process described in US patent No. US6008233, which is mentioned above and incorporated herein by reference in its entirety.

Referring to scheme 2, the threo-type compound of formula (IVA) is debenzylated by any means known to those skilled in the art, preferably by exposure to hydrogenolysis conditions, most preferably in the presence of hydrogen in tetrahydrofuran and at 45-50 ℃ for 5-6 hours under palladium on carbon. Other effective ways of removing benzyl groups will be appreciated by those skilled in the art.

Route 2

The product of the above reduction, a racemic mixture of enantiomers of formula (I) and (II), is then resolved by formation of D- (-) -tartrate and selective crystallization. The D- (-) -tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol (VA) can be directly prepared from an anhydrous methanol solution of the racemates (I and II) by heating the methanol solution to about 50-55 ℃ and then slowly adding a solution of D- (-) -tartaric acid in water. The mixture is thereafter heated to about 60-65 deg.C, and the formation of the D- (-) -tartrate salt may optionally be promoted by the addition of a small amount of the D- (-) -tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol. The mixture was held at reflux temperature (60-65 ℃) for about 4 hours, during which time a thick suspension formed. The slurry was slowly cooled and the solids were collected by filtration and washed with methanol. This procedure yielded a D- (-) -tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol with equal to or less than 2% enantiomeric or diastereomeric impurities. The ratio of water to methanol should be adjusted to 5-20%, preferably 7-10% water/methanol in the final solution. Table 1 shows that the enantiomeric purity of the D- (-) -tartrate salt can be significantly improved by using aqueous methanol instead of anhydrous methanol as the solvent, and as shown in table 1, up to two repulpings or recrystallizations may be required to obtain a similar level of enantiomeric purity of the D- (-) -tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol.

TABLE 1 comparison of resolution of the racemates (Compounds I and II) with D- (-) -tartrate in methanol and aqueous methanol

D-tartaric acidReaction of

Solvent(s)

Molar equivalent (mL/g crude time temperature yield required weight% - (1R, 2R) -to

I/II) antipode of pulping

1.0 methanol (20) 3 hours at 65 ℃ 78% 11.8%

1.0 methanol (20) 3 hours at 65 ℃ 78% 12.0%

1.0 methanol (20) 5 hours at 65 ℃ 76% 21.2%

1.0 methanol (20) 5.5 hours 65 ℃ 73% 21.7%

1.03 methanol (18) 3.5 h 65 ℃ 88% 02.5%

Water (1.6)

1.03 methanol (18)/3.5 h 80% 01.1% at 65 ℃

Water (1.6)

The resolution of racemic 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol in aqueous methanol to the D- (-) -tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol, especially free of the corresponding (1R, 2R) and other diastereomers, is illustrated in example 1. Example 2 provides a reference process using anhydrous methanol as solvent.

Route 3

Referring to scheme 3, the mesylate trihydrate of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol can be directly formed from the D- (-) -tartrate salt by dissolving the D- (-) -tartrate salt in water present in 1.00 to 1.15 molar equivalents, preferably 1.05 to 1.10 molar equivalents of methanesulfonic acid, heating the mixture to about 60 to 65 ℃, and subsequently filtering the solution to remove any exogenous particulate matter. The hot solution was then slowly cooled to 15-20 ℃ to give a thick white suspension, further cooled to 0-5 ℃ and granulated at 0-5 ℃ for 1 hour. After isolation of the product by filtration, the mesylate salt was dried under an inert atmosphere, washing with cold water (0-5 ℃). Table 2 shows the preparation of the mesylate trihydrate at different molar equivalent ratios of methanesulfonic acid to (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol.

TABLE 2 preparation of Compounds of formula VI from Compounds of formula VA

Yield equivalent water enantiomeric diastereomer

Compound (VA) CH₃SO₃H volume Compound (VI) initial Final initial

(mol) (Mol) (mL/g VA)

1.01.03.589.0% (haze) 1.7% 0.19% 0.4% 0.13

1.01.053.590.4% (haze) 1.7% 0.05% 0.4% 0.08

1.0 1.10 3.5 93.8％ 1.7％ 0.05％ 0.4％ 0.08

1.0 1.15 3.25 92.4％ 2.5％ 0.07％ 0.2％ -

1.0 1.10 4.0 84.8％ 3.2％ 0.18％ - ＜0.1％

1.0 1.15 3.25 87.0％ 4.4％ 0.68％ 0.2％ 0.18

VI recrystallization 1.591.9% 0.68% 0.1% 0.18% 0.02

Similar to the anhydrous methanesulfonate salt and the free base, the methanesulfonate trihydrate has a selective neuroprotective effect based on its anti-ischemic activity and its ability to block excitatory amino acid receptors. Preferred methods for assessing the neuroprotective effect of this compound are described in Ismail A. Shalaby et al, J. Pharmacology & Experimental therapeutics 260, 925 (1992). This document is incorporated herein by reference in its entirety and as described below.

Cell cultureDay 17 fetal mice (CD, Charles River Breeding laboratories, Inc., Wilmington, Mass.) Hippocampus cells were cultured on PRIMARIA culture plates (Falcon Co., lincoln Park, N.J.) in serum containing medium (containing optional media)Minimal essential medium for amino acids containing 2mM glutamine, 21mM glucose, penicillin/streptomycin (5000U each), 10% fetal bovine serum (1-17 days) and 10% horse serum (1-21 days)). Cells were plated either at a density of 80,000 cells/well on 96-well microtiter plates or at a density of 250,000 cells/well on 24-well culture plates. Cultures were incubated at 37 ℃ in 5% CO₂Per95% air humidified CO₂And (4) growing in a tissue culture incubator. Proliferation of non-neuronal cells was controlled by adding 20 μ M uridine and 20 μ M5-fluoro-2-deoxyuridine (Sigma Chemical Co., St.Louis, Mo.) to the cultures on days 6 to 8. The culture medium was replaced with fresh stock solution every 2 to 2 days.

Glutamate toxicityGlutamate toxicity to the cultures was performed from 2-4 weeks from the start of plating. The culture medium was removed and the culture was rinsed 2 times with CSS (in millimoles): NaCl 12-; KCl, 5.4; MgCl₂，0.8；CaCl₂1.8; glucose, 15; and 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid, 25mM (pH 7.4). The cultures were then exposed to glutamate at various concentrations for 15 minutes (37 ℃). After incubation, the cultures were rinsed 3 times with glutamate-free CSS and 2 times with serum-free fresh medium. The culture is subsequently cultured in serum-free medium for 20 to 24 hours. Compounds were tested 2 minutes after addition and during 15 minutes exposure to glutamate. In some experiments, the compound was added at different times after exposure to glutamate and then 20-24 hours.

Cell viability is generally assessed within 20-24 hours after excitotoxin (exitotoxin) exposure by measuring the activity of the cytosolic enzyme LDH (lactate dehydrogenase). LDH activity was determined from the medium in each well of a 96-well microtiter plate. A50. mu.l sample of the medium was added to an equal volume of sodium phosphate buffer (0.1M, pH 7.4) containing 1.32mM sodium pyruvate and 2.9mM NADH. The absorbance at 340nm of the total reaction mixture in each well of 96 wells was monitored every 5 seconds over 2 minutes using an automated spectrophotometric microtiter plate reader (Molecular Devices; Menlo Park, Calif.). Absorbance was automatically calculated using the IBM SOFTMax program (version 1.01; Molecular Devices) and used as an indicator of LDH activity.

Morphological assessment of neuronal viability was determined using fragment contrast microscopy. The 96-well plates do not give good contrast imaging of the fragments and for this purpose the culture is carried out on 24-well plates. Quantitatively, both culture plates were equally sensitive to glutamate toxicity and LDH activity increased 2 to 3-fold after 24 hours exposure to 0.1 to 1.0mM glutamate.

ReagentDTG is commercially available from Aldrich Chemical Company (Milwaukee, Wis.), and haloperidol is available from Research Biochemicals In (Natick, Mass.). Spermine is available from Sigma Chemical co. (st. louis Mo.). Horse and fetal bovine serum were purchased from Hyclone (Logan, Utah). Media, glutamine and penicillin/streptomycin were purchased from Gibco Co (Grand Island, n.y.).

Data analysisNeurotoxicity can be quantified by measuring the activity of LDH present in the medium after 20 to 24 hours of exposure to glutamate. Increased LDH activity in culture media has been associated with neuronal destruction and degeneration (Koh)&Choi, 1987). Since the actual levels of LDH vary from culture to culture, data are usually presented relative to buffer treatment of sister wells of the same culture plate. To obtain an indication of LDH activity from glutamate and drug treated cultures, LDH values of control cultures should be subtracted from LDH values of the treated groups. For each test drug, the data for treatment are expressed as a percentage of LDH increase induced by 1mM glutamate (or NMDA). The NMDA antagonist concentration required to reverse half of the excitotoxin-induced LDH increment was calculated from the combined results of three independent experiments using log-probability unit analysis.

The selective neuroprotective anti-ischemic and excitatory amino acid blocking activity of the mesylate trihydrate salt of the invention makes it useful in the treatment of a disease selected from the group consisting of: degenerative CNS disorders such as stroke, alzheimer's disease, parkinson's disease and huntington's disease; epilepsy, anxiety, cerebral ischemia, muscle spasm, multi-infarct dementia, traumatic brain injury, pain, AIDS-related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal syndrome, psychiatric disorders, and urinary incontinence.

In the systemic treatment of the above-mentioned diseases, the dose is generally about 0.02 to 250 mg/kg-day (0.001 to 12.5 g/day in a typical human body having a body weight of 50 kg), and the dose may be administered once or in divided doses, regardless of the administration route. A more preferred dosage range is from about 0.15 mg/kg-day to about 250 mg/kg-day. Obviously, depending on the exact nature of the disease and the condition of the patient, the attending physician may prescribe dosages outside this range. The oral route of administration is generally preferred, in the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders, and the like; or parenterally, in the form of injectable solutions or suspensions, etc.; and topical administration in the form of solutions, lotions, ointments, salves, etc.

The following examples illustrate the process of the invention and the preparation of the compounds of the invention. The melting point was not corrected. NMR data are in parts per million (ppm) (δ) and referenced to sample solvent (deuterated dimethyl sulfoxide (d)₆-DMSO) unless otherwise indicated). The commercially available reagents used were not further purified.

Example 1

Resolution of 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-benzene with D- (-) -tartaric acid in aqueous methanol

Arylpiperidin-1-yl) -1-propanol

Rac-1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol (78.0kg, 207.7mol) and dry methanol (1223L) were added to a clean reaction kettle maintained under a nitrogen atmosphere. The compound was stirred and heated to 50-55 ℃. After the solution was kept at 50-55 ℃ for 1 hour, D- (-) -tartaric acid was added over 10 minutesA solution of acid (32.1kg, 214mol) in water (105L). The reaction was heated to 60-65 ℃ and the D- (-) -tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol present in methanol (0.5L) was added. The solution was held at reflux (60-65 ℃) for 4 hours, during which time a thick suspension formed. The slurry was cooled to 30-35 ℃ over 1.5 hours and filtered at 30-35 ℃. The filter cake was washed with methanol (204L) and then dried under vacuum at 40-45 deg.C for 20-30 hours. The D- (-) -tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol was isolated in a yield of 40% by weight (80% of theory). [ alpha ] to]_D ²⁵35.2(0.0185, water). Chiral HPLC showed that the solid contained 1.2% of the (1R, 2R) -enantiomer and 0.8% of the (1R, 2S) -and (1S, 2R) -diastereoisomers.

Example 1

Resolution of 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-benzene with D- (-) -tartaric acid in anhydrous methanol

Arylpiperidin-1-yl) -1-propanol

To an appropriate flask maintained under a nitrogen atmosphere was added 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol (189.5g, 0.58mol) and methanol (3.8L). The mixture was heated to 50-55 ℃ followed by heating D- (-) -tartaric acid (87.0g, 0.58 mol). The mixture was heated at reflux (. about.65 ℃) for 5 hours. The slurry was allowed to cool to 30-35 ℃ and then granulated at 30-35 ℃ for 1 hour. The product was filtered off and the filter cake was washed with fresh methanol (135 ml). Samples from the wet cake were taken for chiral HPLC analysis to determine the level of enantiomeric purity. The wet cake was suspended in methanol (1.6L) and the resulting slurry heated under reflux (. about.65 ℃ C.) and nitrogen for 5 hours. The slurry was cooled to 30-35 ℃ and granulated at 30-35 ℃ for 1 hour, followed by filtration. The filter cake was washed with methanol (136L) and then dried under vacuum at 40-45 deg.C for 18-24 hours. Samples were taken for chiral HPLC analysis. This gave (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol (118.0g) as the D- (-) -tartrate salt. Thus, as a result shown in table 1, one additional methanol secondary slurry was required to reduce the amount of (1R, 2R) -enantiomeric impurity to less than 2.5%.

Example 3

(1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanolmethanesulfonic acid

Preparation of acid salt trihydrate

The D- (-) -tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol (5.0g, 10.5mmol), water (17.5ml) and polymer (1.05g, 11.0mmol) were mixed in a 50ml three neck round bottom flask under nitrogen atmosphere. The slurry was heated to 60-65 ℃ to obtain a solution, and the solution was filtered. The filtrate was slowly cooled to 15-20 ℃ over 1 hour to give a thick white suspension. The slurry was further cooled to 0-5 ℃ and granulated at 0-5 ℃ for 1 hour. The product was filtered, the filter cake washed with 2.5ml cold water (0-5 ℃) and subsequently dried under a stream of nitrogen at 20-25 ℃. The (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol methanesulfonate trihydrate was isolated (4.53g) in an overall yield of 90.4% as a white crystalline solid. The physical and chemical properties of the isolated trihydrate were identical to those of the real sample:¹H NMR(d₆-DMSO)δ9.58(s，1H)，8.91(S，1H)，7.48(m，2H)，7.35(m，2H)，7.21(m，3H)，6.77(d，J＝8.5Hz，2H)6.35(s，1H)，5.52(s，1H)，4.58(d，J＝8.1Hz，1H)，3.40(m，11H)，2.63(m，1H)，2.3(s，3H)，1.78(m，2H)，0.95(d，J＝6.6Hz，3H)。¹³C NMR(d₆-DMSO) δ 158.13, 148.61, 132.27, 129.27, 128.80, 127.51, 125.26, 115.89, 72.12, 68.89, 66.30, 47.40, 42.91, 35.71, 35.37. Calculated value C₂₀H₂₅NO₃·CH₃SO₃H·3H₂O: c, 52.81; h, 7.39; n, 2.93; s, 6.71. Measured value: c, 52.77; h, 7.50; n, 2.94; s, 6.96. alpha_D+ 54.5. (anhydrous basis).

If low pyrogen and pyrogen-free conditions are used in the above process, (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol is suitable for the preparation of parenteral medicaments. Table 2 reports the trihydrate prepared with different equivalents of methanesulfonic acid. It is clear that when using low equivalent weight methanesulfonic acid (1.0-1.05), the product trihydrate has a residual haze (trace insolubles) when dissolved in water, a characteristic which is unacceptable for parenteral formulations.

Claims (5)

1. A process for preparing a D- (-) -tartrate salt of a compound of formula (I):

the method comprises the following steps:

(i) mixing a racemic mixture containing compounds of formula (I) and (II)

Dissolving in aqueous methanol in the presence of D- (-) -tartaric acid; and

(ii) the D- (-) -tartrate salt of the compound of formula (I) is isolated from this solution.

2. The process according to claim 1, wherein the aqueous methanol has a water content of 5 to 20%.

3. The process according to claim 1, wherein the aqueous methanol has a water content of 7 to 10%.

4. A D- (-) -tartrate salt of a compound of formula (I):

wherein the ratio of the (1S, 2S) -enantiomer to its (1R, 2R) -enantiomer is greater than 97%.

5. A salt according to claim 4 wherein the ratio of the (1S, 2S) -enantiomer to its (1R, 2R) -enantiomer is greater than 98%.