METHOD FOR THE PRODUCTION OF PRAZIQUANTEL AND PRECURSORS THEREOF
20180251428 ยท 2018-09-06
Assignee
Inventors
- Luc Eberhardt (Wiesbaden, DE)
- Andreas WAECHTLER (Darmstadt, DE)
- David Maillard (Darmstadt, DE)
- Stefan LEHMANN (Otzberg, DE)
Cpc classification
B01J31/2409
PERFORMING OPERATIONS; TRANSPORTING
B01J31/2452
PERFORMING OPERATIONS; TRANSPORTING
Y02A50/30
GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
C07D401/04
CHEMISTRY; METALLURGY
B01J31/122
PERFORMING OPERATIONS; TRANSPORTING
International classification
B01J31/24
PERFORMING OPERATIONS; TRANSPORTING
B01J31/12
PERFORMING OPERATIONS; TRANSPORTING
Abstract
The present invention provides methods of preparing Praziquantel, in particular (R)-Praziquantel and analogues thereof in a stereoselective manner. One method involves asymmetric hydrogenation of the following intermediate compound
##STR00001##
and subsequent cyclization.
Claims
1. A method of preparing (i) an optically active compound according to the following Formula (X1) ##STR00041## or (ii) an optically active compound according to the following Formula (X2) ##STR00042## or (i) a mixture of the two, wherein R is selected from C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, and unsubstituted or substituted aryl, comprising: subjecting a compound according to the following Formula (Y) ##STR00043## with R as above, to a hydrogenation step.
2. Method according to claim 1, wherein R is methyl or cyclohexyl.
3. Method according to claim 1, wherein the mixture comprises either the compound according to Formula (X1) or the compound according to Formula (X2) in excess and wherein the hydrogenation step is an asymmetric hydrogenation step in the presence of a catalyst.
4. Method according to claim 3, wherein the compound according to Formula (X1) is present in the mixture in an enantiomeric excess of at least 10%, preferably at least 20%, more preferably at least 30%, at least 40%, at least 50%, at least 60, at least 70%, most preferably at least 80%.
5. Method according to claim 3, wherein the catalyst is an iridium based catalyst.
6. Method according to claim 5, wherein the catalyst comprises an iridium compound in combination with a chiral phosphine ligand.
7. Method according to claim 5, wherein the iridium based catalyst is or comprises a mixture of [Ir(COD)Cl].sub.2 and a ligand selected from TABLE-US-00005
8. Method according to claim 3, wherein the asymmetric hydrogenation step in the presence of a catalyst is carried out involving at least one of: elevated temperature, which temperature is preferably at least 60 C., for instance at least 80 C., at least 90 C. or at least 100 C.; a solvent selected from dioxane, THF, Me-THF, IPA, DCE, DCM, ethyl acetate, toluene, ,,-trifluorotoluene, xylene, preferably m-xylene or p-xylene, mesitylene or a mixture of any two or more thereof; at least one additive, which is preferably selected from iodine (I.sub.2), iodide, phosphoric acid (H.sub.3PO.sub.4), acetic acid (AcOH), HI, HBF.sub.4, preferably in an amount of at least 5 mol %, more preferably at least 50 mol %, more preferably at least 100 mol %; a substrate concentration of at least 0.05 mmol/l, for instance at least 10 mmol/l, at least 100 mmol/l; a catalyst loading of at least 50/1 substrate/catalyst; for instance at least 100/1, at least 250/1, at least 500/1 and elevated pressure, which pressure is preferably at least 1 bar H.sub.2, at least 5 bar H.sub.2, at least 10 bar H.sub.2, at least 20 bar, at least 25 bar H.sub.2, at least 50 bar or at least 100 bar H.sub.2.
9. Method of preparing an enantiomerically pure or enantiomerically enriched compound according to Formula (Q1) or Formula (Q2) ##STR00052## comprising (a) preparing (i) the optically active compound according to the Formula (X1) or (iii) the mixture of compounds according to Formula (X1) and Formula (X2), in which mixture the compound according to Formula (X1) is present in excess, according to the method of claim 1, for the preparation of the compound according to Formula (Q1) or (b) preparing (i) the optically active compound according to the Formula (X2) or (iii) the mixture of compounds according to Formula (X1) and Formula (X2), in which mixture the compound according to Formula (X2) is present in excess, according to the said method from above, for the preparation of the compound according to Formula (Q2), wherein R in Formulae (Q1) and (Q2) is selected from C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, and optionally substituted aryl.
10. Method of preparing the enantiomerically pure or enantiomerically enriched compound according to Formula (Q1) or Formula (Q2) according to claim 9, further comprising (a) reacting (i) the optically active compound according to Formula (X1) or (iii) the mixture of compounds according to Formula (X1) and Formula (X2), in which mixture the compound according to Formula (X1) is present in excess, with a compound YCOCH.sub.2X, wherein Y is F, Cl or Br or OCO-alkyl and X is F, Cl or Br, most preferably with chloroacetyl chloride (ClC(O)CH.sub.2Cl) to give the compound according to Formula (Q1); or (b) reacting the optically active compound according to the Formula (X2) or (iii) the mixture of compounds according to Formula (X1) and Formula (X2), in which mixture the compound according to Formula (X2) is present in excess, with a compound YCOCH.sub.2X, wherein Y is F, Cl or Br or OCO-alkyl and X is F, Cl or Br, most preferably with chloroacetyl chloride (ClC(O)CH.sub.2Cl) to give the compound according to Formula (Q2).
11. Method of preparing an enantiomerically pure or enantiomerically enriched compound according to Formula (Q1) or Formula (Q2) ##STR00053## comprising preparing a mixture of compounds according to Formula (X1) or Formula (X2) according to the method of claim 1, separating the compound according to Formula (X1) from the compound according to Formula (X2), and reacting (a) the compound according to Formula (X1) with a compound YCOCH.sub.2X, wherein Y is F, Cl or Br or OCO-alkyl and X is F, Cl or Br, most preferably with chloroacetyl chloride (ClC(O)CH.sub.2Cl, to obtain the enantiomerically pure or at least enantiomerically enriched compound according to Formula (Q1); or (b) the compound according to Formula (X2) with a compound YCOCH.sub.2X, wherein Y is F, Cl or Br or OCO-alkyl and X is F, Cl or Br, most preferably with chloroacetyl chloride (ClC(O)CH.sub.2Cl, to obtain the enantiomerically pure or at least enantiomerically enriched compound according to Formula (Q2), wherein R is the same in Formulae (Q1) and (Q2) as in Formulae (X1) and (X2).
12. Method of preparing enantiomerically pure or enantiomerically enriched (R)-Praziquantel ##STR00054## comprising the method according to claim 9, using the optically active compound according to Formula (X1) or (iii) the mixture of compounds according to Formula (X1) and Formula (X2), in which mixture the compound according to Formula (X1) is present in excess, wherein R is cyclohexyl in the compound according to Formula (X1).
13. Method of preparing a mixture of an optically active compound according to the following Formula (X1) and an optically active compound according to the following Formula (X2) ##STR00055## or salts thereof, wherein R is selected from C.sub.1-C.sub.8 alkyl and C.sub.3-C.sub.8 cycloalkyl; wherein the compounds or salts thereof are present in said mixture in a first ratio of RM1=X1:X2, which is from 0.8 to 1.2, preferably from 0.9 to 1.1 and most preferably 1; comprising the following steps: (a) dehydrogenating a mixture of compounds according to Formulae (X1) and (X2), wherein the compounds are present in said mixture in a second ratio RM2=X1:X2, which is either smaller than 0.8 or larger than 1.2, to produce a mixture of compounds according to the following Formula (Y) and to Formula (Z), wherein R is the same as in Formulae (X1) and (X2) ##STR00056## or salts thereof and (b) hydrogenating said mixture of compounds according to Formula (Y) and to Formula (Z) or salts thereof to obtain the mixture of compounds of Formulae (X1) and (X2) or salts thereof in the first ratio RM1, wherein the mixture of compounds according to Formulae (X1) and (X2) or salts thereof in the second ratio RM2 is preferably prepared either by asymmetric hyrogenation of a compound according to Formula (Y) in accordance with the method according to claim 3 or by separation of a mixture of compounds according to Formulae (X1) and (X2), which mixture was preferably prepared according to the method.
14. A compound according to the following Formula (Y1) ##STR00057##
15. A method for the preparation of (i) an optically active compound according to the following Formula (X1) ##STR00058## or (ii) an optically active compound according to the following Formula (X2) ##STR00059## or (iii) a mixture of the two, with R being selected from C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, and optionally substituted aryl, most preferably cyclohexyl, comprising a reaction of a compound of Formula (Y) ##STR00060##
16. A method for the preparation of (R)-Praziquantel comprising a reaction of a compound of Formula (Y1) according to claim 14.
17. Method of preparing a compound of Formula (Y1) according to claim 14 ##STR00061## comprising reacting [isoquinolin-1-yl)-methyl]-amine ##STR00062## with a cyclohexane carboxylic acid based acylating agent.
Description
EXAMPLE 1: SYNTHESIS OF (R)-PRAZIQUANTEL: ROUTE 1
Step 1: Preparation of Isoquinaldonitrile (2)
[0109] ##STR00030##
[0110] Isoquinaldonitrile (2) is commercially available and can be prepared from isoquinoline (1) according to reported procedures, such as the following: J. M. Wefer, A. Catala, F. D. Popp, Chem. Ind. (London) 1965, 140-141; J. M. Wefer, A. Catala, F. D. Popp, J. Org. Chem. 1965, 30, 3075-3077; M. D. Rozwadowska, D. Brozda, Can. J. Chem. 1980, 58, 1239-1242 and D. L. Boger, C. E. Brotherton, J. S. Panek, D. Yohannes, J. Org. Chem. 1984, 49, 4056-4058, which are incorporated herein by reference in their entirety.
Step 2: Preparation of [(Isoquinolin-1-yl)-methyl]amine (3)
[0111] ##STR00031##
[0112] 18 g (0.117 mol) Isoquinaldonitrile (2) are dissolved in ethanol (250 g) and 18.6 g hydrochloric acid (32%) under stirring at room temperature. After addition of 7.8 g wet palladium-charcoal (5%), atmospheric pressure of hydrogen is applied for 17 h. Afterwards, the resulting mixture is filtered over celite and the filtrate concentrated in vacuo. The residue is then dissolved in a biphasic mixture of dichloromethane (150 g) and 32%-NaOH aqueous solution (55 g). The phases are separated and the aqueous layer is extracted three times with dichloromethane (200 g). The combined organic layers are finally evaporated affording [(isoquinolin-1-yl)-methyl]-amine (3) as a light brown solid (20.4 g, 90% yield).
[0113] Characterization of [(Isoquinolin-1-yl)-methyl]amine:
[0114] C.sub.10H.sub.10N.sub.2 (158.20 g.Math.mol.sup.1), mp. 211-212 C.
[0115] .sup.1H NMR (d.sup.6-DMSO): 8.47 (d, J=5 Hz, 1H.sub.arom), 8.26 (d, J=8 Hz, 1H.sub.arom), 7.96 (d, J=8 Hz, 1H.sub.arom), 7.77 (t, J=6 Hz, 1H.sub.arom), 7.71 (d, J=5 Hz, 1H.sub.arom), 7.67 (t, J=6 Hz, 1H.sub.arom), 4.39 (s, 2H), 2.70 (bs, NH.sub.2)
Step 3: Preparation of N-(1-isoquinolin-1-yl-methyl)-cyclohexane Carboxylic Acid-Amide (4)
[0116] ##STR00032##
[0117] 58.9 g (0.372 mol) [(Isoquinolin-1-yl)-methyl]amine (3) are dissolved in THF (250 g) under stirring at room temperature. 51.2 g (0.410 mol) of 32%-NaOH aqueous solution and water (150 g) are added. The mixture is cooled down to 10 C. before dropwise addition of a solution of 60 g (0.410 mol) cyclohexane carboxylic-acid chloride in THF (50 g) within 2.5 h at 10-15 C. The resulting biphasic mixture is stirred at room temperature for 2 h before addition of 2N HCl (191 g). 300 g Methyl-THF and 350 g water are added to enable phase separation, the aqueous layer is separated and the organic phase is extracted twice with 1N HCl (190 g). The aqueous phases are combined, washed with methyl-THF (200 g) and then neutralized with 32%-NaOH aqueous solution (106 g). Methyl-THF (200 g) is added, the phases are separated, the aqueous phase is extracted twice with methyl-THF (200 g), the combined organic phases are finally evaporated and the crude solid residue is recrystallized from ethyl acetate affording N-(1-isoquinolin-1-yl-methyl)-cyclohexane carboxylic acid-amide (4) as a white to light yellow solid after drying (69.9 g, 70% yield). Second crop crystals can be isolated through recrystallization of mother liquor residue from ethyl acetate (15 g, total yield 85%).
[0118] Characterization of N-(1-isoquinolin-1-yl-methyl)-cyclohexane carboxylic acid-amide:
[0119] C.sub.17H.sub.20N.sub.2O (268.36 g.Math.mol.sup.1), mp. 126-128 C.
[0120] .sup.1H NMR (CDCl.sub.3): 8.44 (d, J=6 Hz, 1H.sub.arom), 8.12 (ddd, J=9 Hz, J=3 Hz, J=0.5 Hz, 1H.sub.arom), 7.85 (dt, J=9 Hz, J=0.5 Hz, 1H.sub.arom), 7.59-7.75 (m, 3H.sub.arom), 7.55 (bs, NH), 5.06 (d, J=6 Hz, 2H), 2.31 (tt, J=9 Hz, J=3 Hz, 1H), 1.96-2.03 (m, 2H), 1.80-1.87 (m, 2H), 1.67-1.73 (m, 1H), 1.50-1.57 (m, 2H), 1.22-1.39 (m, 3H)
[0121] .sup.13C NMR (CDCl.sub.3): 176.2 (s, 10=0), 154.8 (s, 1qC.sub.arom), 140.9 (s, 1C.sub.arom)) 136.0 (s, 1qC.sub.arom), 130.4 (s, 1C.sub.arom), 127.8 (s, 1C.sub.arom), 127.3 (s, 1C.sub.arom), 125.9 (s, 1qC.sub.arom), 123.9 (s, 1C.sub.arom), 120.4 (s, 1C.sub.arom), 45.6 (s, CH), 41.9 (s, 1CH.sub.2), 29.8 (s, 2CH.sub.2), 25.9 (s, 3CH.sub.2)
[0122] MS (EI) m/z (%): 268 (19) [M], 250 (18), 221 (10), 195 (19), 185 (27), 182 (15), 157 (100), 142 (36), 130 (11), 115 (28), 77 (4)
Step 4: Preparation of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic Acid-Amide (5(R))
[0123] ##STR00033##
[0124] 11.51 mg (0.019 mmol) Catalyst precursor [Ir(COD)Cl].sub.2 and 26.17 mg (0.041 mmol) (S)-Xyliphos are mixed together and dissolved in THF (5 g) in an inertized glove box. 0.2 g (0.75 mmol) N-(1-isoquinolin-1-yl-methyl)-cyclohexane carboxylic acid-amide (4) are dissolved in THF (25 g) in an autoclave under nitrogen at room temperature. The catalyst solution is added with a syringe to the autoclave before applying a hydrogen pressure of 100 bar and heating up to 75 C. The pressure rose up to 110 bar over the 24 h reaction time affording a conversion of 56% for the targeted [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid-amide (5(R)), which is also referred to as (R)-PZQ-Carboxamide herein, with an enantioselectivity of ee=64%. The reaction mixture can finally be evaporated, purified through chromatography and finally crystallized from n-heptane/ethanol to improve the ee of (R)-PZQ-Carboxamide (5(R)) up to 96%.
[0125] Characterization of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclo-hexane-carboxylic acid-amide:
[0126] C.sub.17H.sub.24N.sub.2O (272.39 g.Math.mol.sup.1), mp. 110-112 C.
[0127] NMR data were in full accordance with the data of the racemate (see below).
Step 5: Preparation of (R)-Praziquantel
[0128] ##STR00034##
[0129] (R)-Praziquantel ((R)-PZQ) (6) can be prepared from [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid-amide (5(R)) ((R)-PZQ-Carboxamide) through cyclization with chloro-acetyl chloride according to known procedures, such as the procedure described by Sergovskaya and Chernyak (1991), as reproduced by Roszkowski, P. et al. in Tetrahedron: Asymmetry 17 (2006) 1415-1419: To a stirred solution of amine (1R)-7 [in the present case (5(R))] (110 mg, 0.39 mmol) in 1.0 mL CH.sub.2Cl.sub.2, a solution of 50% NaOH (0.12 mL, 1.33 mmol) was added, followed by the addition of a solution of chloroacetyl chloride (0.034 mL, 0.43 mmol) in 0.15 mL of CH.sub.2Cl.sub.2. After 0.5 h, TEBAC (9 mg, 0.04 mmol) was added and the mixture was heated and stirred for 2 h at reflux. After that time, a portion of 3 mL of water was added and the mixture extracted with CH.sub.2Cl.sub.2 (23 mL). The organic phase was washed with water (22 mL), 5% HCl (2 mL), again with water (2 mL) and dried over Na2SO4. After evaporation of the solvent, the residue was purified with column chromatography on silica gel using chloroform/methanol 0-0.3% MeOH as a solvent system to afford 93 mg (77%) of (1R)-()-8 [in the present case (R)-PZQ].
[0130] Characterization of (R)-PZQ:
[0131] C.sub.19H.sub.24N.sub.2O.sub.2 (312.42 g.Math.mol.sup.1), mp. 110-111 C.
[0132] Analytical data already known and described.
EXAMPLE 2: SYNTHESIS OF (R)-PRAZIQUANTEL: ROUTE 2
Steps 1 to 3 in the Preparation of N-(1-isoquinolin-1-yl-methyl)-cyclohexane Carboxylic Acid-Amide (4) are the Same as in ROUTE 1
Step 4: Preparation of N-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-cyclohexanecarboxylic Acid-Amide (5)
[0133] ##STR00035##
[0134] 21 g (0.078 mol) N-(1-isoquinolin-1-yl-methyl)-cyclohexane carboxylic acid-amide (4) are dissolved in methanol (MeOH, 145 g) and glacial acetic acid (AcOH, 2.18 g, 0.036 mol) under stirring at room temperature. After addition of 11.8 g wet platinum on activated charcoal (5%) (PtC), a hydrogen (H.sub.2) pressure of 2.6 bar and a temperature of 35 C. are applied for 16 h, the mixture is afterwards filtered over celite and the filtrate concentrated in vacuo. The residue is taken up in dichloromethane (200 g), washed with NaOH (5%) until a pH of 12-13 has been reached. After phase separation, the aqueous layer is extracted with dichloromethane (90 g), the combined organic phases are washed three times with water (75 g) reaching a pH of 7 and finally evaporated. The residue is recrystallized from ethyl acetate affording a racemic mixture of N-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-cyclohexanecarboxylic acid-amide (5) as light yellowish crystals after drying (14.5 g, 68% yield).
[0135] Characterization of N-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-cyclohexane-carboxylic acid-amide:
[0136] C.sub.17H.sub.24N.sub.2O (272.39 g.Math.mol.sup.1), mp. 106-108 C.
[0137] .sup.1H NMR (CDCl.sub.3): 7.12-7.03 (m, 3H.sub.arom), 7.03-6.93 (m, 1H.sub.arom), 6.27 (t, J=6 Hz, NH), 3.97 (dd, J=9 Hz, J=5 Hz, 1H), 3.71-3.63 (m, 1H), 3.30-3.20 (m, 1H), 3.09-3.00 (m, 1H), 2.98-2.89 (m, 1H), 2.70-2.63 (m, 2H), 2.05-1.94 (m, 2H), 1.78-1.53 (m, 5H), 1.41-1.25 (m, 2H), 1.25-1.07 (m, 3H)
[0138] .sup.13C NMR (CDCl.sub.3): 176.4 (s, 1CO), 136.0 (s, 1qC.sub.arom), 135.4 (s, 1C.sub.arom)) 129.3 (s, 1C.sub.arom)) 126.5 (s, 1C.sub.arom), 126.4 (s, 1C.sub.arom), 126.1 (s, 1C.sub.arom), 55.0 (s, 1CHN), 45.5 (s, 1CH), 43.3 (s, 1CH.sub.2), 39.8 (s, 1CH.sub.2), 29.7 (s, 2CH.sub.2), 29.6 (s, 1CH.sub.2), 25.7 (s, 3CH.sub.2)
[0139] MS (EI) m/z (%): 273 (100) [M+H].sup.+
Step 5: Chiral Resolution of Racemic N-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-cyclohexanecarboxylic Acid-Amide (5)
[0140] ##STR00036##
[0141] Racemic N-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-cyclohexanecarboxylic acid-amide (5) can be resolved via formation and crystallization of diastereomeric salts with D-()-tartaric acid from ethanol. After release of the diastereomeric salt under basic conditions (NaOH), extractions with dichloromethane and evaporation in vacuo, [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclo-hexane-carboxylic acid-amide (5(R) is obtained as a white solid with 60% yield and 96% ee.
[0142] A further suitable procedure is described, for instance, in DE2504250 (Example 91): A solution of 16.5 g (D)-()-tartaric acid in 300 mL methanol is added to a solution of 21.7 g racemic N-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-cyclohexanecarboxylic acid-amide (prepared differently in DE2504250) in 300 mL methanol. The solvent is distilled off, and the residue from ethanol recrystallized until the melting point has increased to about 207 C. The salt is dissolved in water, the solution rendered alkaline and then extracted with chloroform or dichloromethane. After drying over magnesium sulphate and distilling off the solvent, [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexane-carboxylic acid-amide (5(R) is obtained.
[0143] Characterization of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclo-hexane-carboxylic acid-amide:
[0144] C.sub.17H.sub.24N.sub.2O (272.39 g.Math.mol.sup.1), mp. 110-112 C.
Step 6 (optional): Recycling of [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexane-carboxylic Acid-Amide
[0145] [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexane-carboxylic acid-amide or mixtures of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexane-carboxylic acid-amide and [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexane-carboxylic acid-amide with an excess of the (S)-configured compound can be recycled via dehydrogenation and rehydrogenation to produce a racemic mixture of the compounds for further chiral resolution as follows:
##STR00037##
[0146] The mother and wash liquor from the chiral resolution step 5 described above are evaporated, treated with dichloromethane and aqueous sodium hydroxide. After extractions of the aqueous layer with dichloromethane, the combined organic layers are evaporated in vacuo affording a mixture of and [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexane-carboxylic acid-amide and some residual [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexane-carboxylic acid-amide.
[0147] 5 g (0.018 mol) of the evaporation residue are dissolved in acetonitrile (30 g) and 2.5 g PdC(10%) are added before applying an ethylene pressure of 10 bar, and subsequently heating up to 100 C. for 18 h, whereas the internal pressure in the autoclave reached a maximum of 20 bar. The mixture is finally filtered over celite, the catalyst washed with warm acetonitrile and the resulting filtrate concentrated in vacuo affording 4.5 g of a light brown solid containing a mixture of N-(1-isoquinolin-1-yl-methyl)-cyclohexane carboxylic acid-amide (4) (53.6%) and its dehydro-derivative (7) (44.3%).
[0148] This residual mixture is directly used for hydrogenation and dissolved in methanol (63 g) and acetic acid (0.178 g, 0.003 mol). After addition of 1.8 g (0.008 mol) wet platinum on activated charcoal (5%), a hydrogen pressure of 2.8 bar and a temperature of 36 C. are applied for 7 h, the mixture is afterwards filtered over celite and the filtrate concentrated in vacuo. The residue is taken up in dichloromethane (40 g), washed with NaOH (5%) until a pH of 12-13 has been reached. After phase separation the aqueous layer is extracted with dichloromethane (20 g), the combined organic phases are washed three times with water (30 g) reaching a pH of 7 and finally evaporated. The residue is recrystallized from ethyl acetate affording 1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclo-hexane-carboxylic acid-amide as light yellowish crystals after drying (2.92 g, 65% yield). This material can subsequently be used for a further step of chiral resolution.
Step 7: Preparation of (R)-Praziquantel
[0149] (R)-Praziquantel ((R)-PZQ) (6) can be prepared from [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid-amide as described in Step 5 of EXAMPLE 1.
EXAMPLE 3: SYNTHESIS OF RACEMIC PRAZIQUANTEL
Steps 1 to 4 are the Same as in EXAMPLE 2 (ROUTE 2)
[0150] ##STR00038##
Step 5: Preparation of Racemic Praziquantel
[0151] Racemic Praziquantel (PZQ) is prepared from racemic 1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid-amide in the same manner as described in Step 5 of EXAMPLE 1.
EXAMPLE 4: SYNTHESIS OF [(S)-1-(1,2,3,4-TETRAHYDRO-ISOQUINOLIN-1-YLMETHYL)]-CYCLOHEXANECARBOXYLIC ACID-AMIDE
Steps 1 and 2 are the Same as Steps 1 and 2 in EXAMPLES 1 to 3
Step 3: Preparation of N-Isoquinolin-1-yl-methyl-acetamide
[0152] ##STR00039##
[0153] N-Isoquinolin-1-yl-methyl-acetamide (8) is synthesized by reacting [(Isoquinolin-1-yl)-methyl]-amine (3) with acetic acid-chloride in analogy to the preparation of N-(1-isoquinolin-1-yl-methyl)-cyclohexane carboxylic acid-amide (4) (Step 3 in EXAMPLE 1).
[0154] Characterization of N-Isoquinolin-1-yl-methyl-acetamide:
[0155] C.sub.12H.sub.12N.sub.2O (200.24 g.Math.mol.sup.1), mp. 127.5-130.5 C.
[0156] .sup.1H NMR (CDCl.sub.3): 8.41 (d, J=6 Hz, 1H.sub.arom), 8.10 (ddd, J=9 Hz, J=3 Hz, J=0.5 Hz, 1H.sub.arom), 7.84 (dt, J=9 Hz, J=0.5 Hz, 1H.sub.arom), 7.58-7.75 (m, 3H.sub.arom), 7.55 (bs, NH), 5.05 (d, J=6 Hz, 2H), 2.16 (s, 3H)
[0157] .sup.13C NMR (CDCl.sub.3): 170.2 (s, 1CO), 154.4 (s, 1qC.sub.arom), 140.8 (s, 1C.sub.arom), 135.9 (s, 1qC.sub.arom), 130.4 (s, 1C.sub.arom), 127.8 (s, 1C.sub.arom), 127.3 (s, 1C.sub.arom), 125.8 (s, 1qC.sub.arom), 123.8 (s, 1C.sub.arom), 120.5 (s, 1C.sub.arom), 42.1 (s, 1CH.sub.2), 23.3 (s, 1CH.sub.3)
[0158] MS (EI) m/z (%): 200 (21) [M], 182 (34), 157 (100), 142 (18), 130 (17), 115 (16), 77 (9), 43 (8)
Step 4a: Preparation of [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide
[0159] ##STR00040##
[0160] 15.30 mg (0.025 mmol) catalyst precursor [Ir(COD)Cl].sub.2 and 34.73 mg (0.054 mmol) (R)-Xyliphos are mixed together and dissolved in THF (5 g) in an inertized glove box. 0.2 g (0.99 mmol) N-Isoquinolin-1-yl-methyl-acetamide (8) are dissolved in THF (25 g) in an autoclave under nitrogen at room temperature. The catalyst solution is added with a syringe to the autoclave before applying a hydrogen pressure of 100 bar and heating up to 100 C. The pressure rose up to 110 bar over the 17 h reaction time affording a conversion of 77.5% for the targeted [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide (9) with an enantioselectivity of ee=84%. The reaction mixture can finally be evaporated, purified through chromatography and finally crystallized to improve the ee of targeted [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide (9) up to 96%.
[0161] Characterization of [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide:
[0162] C.sub.12H.sub.16N.sub.2O (204.27 g.Math.mol.sup.1), mp. 55 C.
Step 4b: Preparation of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide
[0163] In the alternative, [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide can be prepared in analogy to step 4a using S-Xyliphos rather than R-Xyliphos.
[0164] [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide and [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide can be used in the further synthesis of compounds that are structurally very similar to Praziquantel or further be used in the synthesis of Praziquantel itself.
EXAMPLE 5: EXAMPLES OF SUITABLE ASYMMETRIC HYDROGENATION CONDITIONS
Example 5.1: Preparation of 1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide
[0165] The following Table 1 illustrates suitable exemplary asymmetric hydrogenation conditions for the preparation of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide and/or [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide:
[0166] Under an inert atmosphere, iridium(I) cyclooctadiene chloride dimer (15.30 mg) and ligand (1 equivalent per iridium atom) were mixed in tetrahydrofuran (5.00 g). After 1 h stirring, this mixture was added to a solution of N-Isoquinolin-1-ylmethyl-acetamide (200.00 mg) in tetrahydrofuran (30.00 g). The blend was stirred under a 110 bar atmosphere of hydrogen overnight at 100 C. After evaporation of the solvent under reduced pressure, a mixture of (R)-()- and (S)-(+)-N-(1,2,3,4-Tetrahydro-isoquinolin-1-ylmethyl)-acetamide was obtained.
TABLE-US-00003 TABLE 1 Pressure H.sub.2 Temp Conversion ee Ir Catalyst Ligand (bar) ( C.) (%) (%) 1 (R)-6,6- 105 100 61 36(R) Bis(diphenylphosphino)- 2,2,3,3-tetrahydro-5,5-bi- 1,4-benzodioxine 2 (S)-5,5-Bis(di(3,5- 110 100 63 46(R) xylyl)phosphino)-4,4-bi- 1,3-benzodioxole 3 (R)-7,7-Bis[di(3,5- 110 100 55 .sup.6(S) dimethylphenylphosphone]- 2,2,3,3-tetrahydro-1,1- spirobiindane 4 (R)-1-{(S)-2-[Bis[3,5-di- 110 75 53 18(S).sup. trifluoromethylphenyl)phos- phine]ferrocenyl}ethyldi- 3,5-xylylphosphine 5 (S)-Xyliphos 110 75 50 62(R) 6 (R)-Xyliphos 110 100 78 84(S).sup.
Example 5.2: Preparation of 1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic Acid-Amide
[0167] The following Table 2 illustrates suitable asymmetric hydrogenation conditions, including catalysts, and also illustrates how the reaction conditions, for instance choice of solvent or additive, can be adjusted to optimize conversion and/or stereoselectivity, in particular in the preparation of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid-amide and/or [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid-amide:
TABLE-US-00004 TABLE 2 1 Catalyst: (R)-Xyliphos 0.2 mmol, catalyst loading 100/1 S/C, 30 bar H.sub.2, solvent 2 mL, [S] = 0.1M, 16 hours Additive Temp Conv Ee (mol %) Solvent ( C.) (%) (%) 1.1 I.sub.2 (5) dioxane:DCM (20:1) 80 46 73 (S) 1.2 I.sub.2 (5) dioxane:DCM (20:1) 100 64 60 (S) 1.3 I.sub.2 (5) PhMe:DCM (20:1) 80 64 69 (S) 1.4 I.sub.2(50) dioxane:DCM (20:1) 100 99 77(S) 1.5 I.sub.2 (100) dioxane:DCM (20:1) 100 100 80 (S) 1.6 I.sub.2 (100) dioxane:PhMe (20:1) 100 100 76 (S) 1.7 I.sub.2 (50) dioxane:PhMe (20:1) 100 100 54 (S) 1.8 I.sub.2 (100) dioxane:PhMe (20:1) 80 100 84 (S) 2 Catalyst: various (see below) 1 mmol, catalyst loading 500/1 S/C, 30 bar H.sub.2, solvent 5 mL, [S] = 0.2M, 16 hours, I.sub.2 50 mol %, 100 C. Conv Ee Catalyst Solvent (%) (%) 2.1 (S)-Xyliphos m-xylene 79 79 (R) 2.2 (S)-Xyliphos p-xylene 100 80(R)) 2.3 (S)-Xyliphos PhCF.sub.3 97 82(R) 2.4 (R)-Xyl-BINAP m-xylene 100 70(R) 2.5 (R)-Xyl-BINAP PhMe:DCM (4:1) 97 76(R) 2.6 (R)-Xyl-BINAP mesitylene 93 67(R) 2.7 (R)-Xyl-BINAP m-xylene-DCM (4:1) 96 64(R) 2.8 (R)-Xyl-BINAP m-xylene-DCM (3:2) 98 50(R) 3 Catalyst: various (see below) 0.05 mmol, catalyst loading 50/1 S/C, 25 bar H.sub.2, solvent Dioxane:DCM 20:1 0.5 ml, [S] = 0.1M, 16 hours, 80 C., I.sub.2 50 mol % Conv Ee Catalyst (%) (%) 3.1 (R)-(S.sub.p)-Josiphos R1 = Ph R2 = Ph 100 45 (R) 3.2 (R)-Xyliphos 100 78 (S).sup. 3.3 (R)-(S.sub.p)-Taniaphos R1 = Ph R2 = Ph 98 52(R) 3.4 (R)-Me-BoPhoz 84 72(R) 3.5 (R)-Me-BoPhoz (3,5-FPh) 27 68(R) 3.6 (R)-C3-TunePhos 97 52(S).sup. 3.7 (R)-Xyl-BINAP 100 79(R) 4 Catalyst: various (see below) 0.05 mmol, catalyst loading 50/1 S/C, 25 bar H.sub.2, solvent mixture with: solvent:DCM 20:1 0.5 mL, [S] = 0.1M, 16 hours, 80 C. Additive 1 Additive 2 Conv Ee Catalyst (mol %) (mol %) Solvent (%) (%) 4.1 (R)-Xyliphos I.sub.2 (50) MeTHF 100 81(S) 4.2 (R)-Xyliphos I.sub.2 (50) THF 99 77(S) 4.3 (R)-Xyliphos I.sub.2 (50) IPA 49 82(S) 4.4 (R)-Xyliphos I.sub.2 (50) H.sub.3PO.sub.4 (100) dioxane 32 78(S) 4.5 (R)-Xyliphos I.sub.2 (50) AcOH(100) dioxane 100 79(S) 4.6 (R)-Xyliphos I.sub.2 (50) HI(100) dioxane 48 80(S) 4.7 (R)-Xyliphos H.sub.3PO.sub.4 (100) dioxane 87 56(S) 4.8 (R)-Xyliphos HI (100) dioxane 99 70(S) 4.9 (R)-Xyliphos HBF.sub.4 (100) dioxane 100 67(S) 4.10 (S)-Me-BoPhoz I.sub.2 (50) dioxane 89 75(S) 4.11 (S)-Me-BoPhoz I.sub.2 (50) THF 99 77(S) 4.12 (S)-Me-BoPhoz I.sub.2 (50) MeTHF 82 77(S) 4.13 (S)-Me-BoPhoz I.sub.2 (50) EtOAc 80 73(S) 4.14 (S)-Me-BoPhoz H.sub.3PO.sub.4 (100) dioxane 45 72(S) 4.15 (S)-Me-BoPhoz HI (100) dioxane 94 74(S) 4.16 (S)-Me-BoPhoz HBF.sub.4 (100) dioxane 63 67(S) 4.17 (R)-Xyl-BINAP I.sub.2 (50) dioxane 100 .sup.80(R) 4.20 (R)-Xyl-BINAP I.sub.2 (50) THF 100 .sup.78(R) 4.21 (R)-Xyl-BINAP I.sub.2 (50) MeTHF 95 .sup.78(R) 4.22 (R)-Xyl-BINAP I.sub.2 (50) PhMe 43 .sup.76(R) 4.23 (R)-Xyl-BINAP I.sub.2 (50) EtOAc 33 .sup.78(R) 4.24 (R)-Xyl-BINAP I.sub.2 (50) H.sub.3PO.sub.4 (100) dioxane 97 .sup.79(R) 4.25 (R)-Xyl-BINAP I.sub.2 (50) AcOH(100) dioxane 100 .sup.78(R) 4.26 (R)-Xyl-BINAP I.sub.2 (50) HI(100) dioxane 89 .sup.75(R) 4.27 (R)-Xyl-BINAP HI (100) dioxane 95 .sup.81(R) Substr. Conc. Temp. Cat Conv Ee [M] [ C.] [mol %] (%) (%) 5 Catalyst: (S)-Xyliphos 1 mmol, catalyst loading 200-500/1 S/C, 30 bar H.sub.2, solvent dioxane 2-5 mL, [S] = 0.2-0.5M, 16 hours, I.sub.2 50 mol % 5.1 0.2 70 0.5 95 76(R) 5.2 0.2 100 0.2 99 80(R) 5.3 0.5 100 0.5 99 74(R) 6 Catalyst: (R)-Xyl-BINAP 1 mmol, catalyst loading 200-500/1 S/C, 30 bar H.sub.2, solvent dioxane 2-5 mL, [S] = 0.2-0.5M, 16 hours, I.sub.2 50 mol % 6.1 0.2 100 0.2 99 78(R) 6.2 0.5 100 0.5 100 71(R)