HK1052000B - Process of preparing tolterodine and analogues there of as well as intermediates prepared in the process - Google Patents

Description

Process for the preparation of tolterodine and analogues thereof and intermediates prepared in this process

Technical Field

The present invention relates to a novel process for the preparation of tolterodine (tolterodine) and analogues thereof, and to novel intermediates prepared in this process.

Background

Tolterodine, namely (R) -N, N-diisopropyl 3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine, is useful for the treatment of urinary incontinence. The main active metabolite of tolterodine, namely (R) -N, N-diisopropyl-3- (2-hydroxy-5-hydroxymethylphenyl) -3-phenylpropanamine, plays an important role in the therapeutic effect of tolterodine. US-A-5,382,600 discloses tolterodine and its analogues (including the corresponding (S) -enantiomer) and processes for preparing them. US-A-5,559,269 discloses active metabolites and analogues. The (S) -enantiomer and its use in the treatment of urinary and gastrointestinal disorders are further described in WO 98/03067.

One of the methods described in US-A-5,382,600 comprises the following steps: preparation of the lactone 3, 4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one, reductive opening of the lactone ring to prepare the corresponding alcohol, reaction of the alcohol with isopropylamine and resolution of the racemate formed to isolate tolterodine.

US-A-5,922,914 discloses an improved process for the preparation of tolterodine by reducing the above lactone to its corresponding alcohol, 3, 4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol, reductively aminating the alcohol, and resolving the racemate formed to isolate tolterodine.

To obtain the desired enantiomer of tolterodine, the racemate produced according to the above-described prior art method must be separated, whereas Andersson, Pher G.et al, J.Org.chem., 1998, 63, 8067-8070 disclose the enantioselective synthesis of tolterodine, which circumvents the need for an enantiomeric separation step. The process comprises copper bromide catalyzed asymmetric addition of 2-methoxy-5-methylphenyl magnesium bromide to 3-phenyl-prop-2-enoyl-oxazolidinone to produce (5S) -phenyl- (3R) - (2-benzyloxy-5-methylphenyl) -3-phenylpropionyl-2-oxazolidinone, hydrolysis of the oxazolidinone to the corresponding propionic acid, reaction with diisopropylamine to form an amide, and reduction of the amide to tolterodine.

Summary of The Invention

The present invention provides an alternative process for the enantioselective synthesis of tolterodine which is more convenient to carry out than the prior art processes listed above and gives the final product in high enantiomeric purity. The key step of the process is the preparation of the above lactone, 3, 4-dihydro-6-methyl-4-phenyl-2H-chromen-2-one (also known as 6-methyl-4-phenylchroman-2-one), in enantiomerically enriched form by enantioselective reaction.

Thus, in a first aspect the present invention provides a process for the enantioselective preparation of a compound of the general formula (Ia) or (Ib) or a salt thereof,

wherein R is₁、R₂And R₃Independently of one another, hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulfamoyl or halogen, R₄And R₅Independently of one another are C_1-6-an alkyl group, the method comprising the steps of:

a) enantioselectively reducing the carbonyl function of the compound of formula (II),

wherein R is₁、R₂And R₃To form an enantiomerically enriched compound of formula (IIIa) or (IIIb):

wherein R is₁、R₂And R₃Is as defined above;

b) subjecting the compound of formula (IIIa) or (IIIb) to sigma migratory rearrangement to form the corresponding enantiomerically enriched compound of formula (IVa) or (IVb):

wherein R is₁、R₂And R₃Is as defined above;

c) subjecting the compound of formula (IVa) or (IVb) to bayer-virger oxidation to form the corresponding enantiomerically enriched compound of formula (Va) or (Vb):

wherein R is₁、R₂And R₃Is as defined above;

d) converting a compound of formula (Va) or (Vb) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib) or a salt thereof; and

e) optionally converting the compound of formula (Ia) or (Ib) in base form into a salt thereof, or converting the salt form into the free base.

In one embodiment of the first aspect of the present invention, step d) comprises:

d1) reacting a compound of formula (Va) or (Vb) with an amine of general formula (VI),

wherein R is₄And R₅To form a corresponding enantiomerically enriched compound of formula (VIIa) or (VIIb):

wherein R is₁、R₂、R₃、R₄And R₅Is as defined above; and

d2) reducing the carbonyl function of the compound of formula (VIIa) or (VIIb) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib).

Optionally, steps d1) and d2) are carried out simultaneously in a one-step reaction.

In another embodiment, step d) comprises:

d 1') reducing the compound of formula (Va) or (Vb) to form the corresponding enantiomerically enriched hydroxy compound of formula (VIIIa) or (VIIIb):

wherein R is₁、R₂And R₃As defined in claim 1; and

d 2') reductively aminating the hydroxy compound of formula (VIIIa) or (VIIIb) with an amine of formula (VI) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib).

In a second aspect, the present invention provides a process for enantioselectively preparing a compound of general formula (Va) or (Vb):

wherein R is₁、R₂And R₃The definition of (A) is as above,

the method comprises the following steps:

a) enantioselectively reducing the carbonyl function of a compound of formula (II) or a salt thereof,

wherein R is₁、R₂And R₃To form an enantiomerically enriched compound of formula (IIIa) or (IIIb):

wherein R is₁、R₂And R₃Is as defined above;

b) subjecting the compound of formula (IIIa) or (IIIb) to sigma migratory rearrangement to form the corresponding enantiomerically enriched compound of formula (IVa) or (IVb) or a salt thereof;

wherein R is₁、R₂And R₃Is as defined above, and

c) subjecting the compound of formula (IVa) or (IVb) to Bayer-Virgo oxidation to form the corresponding enantiomerically enriched compound of formula (Va) or (Vb) or a salt thereof.

The compounds of formula (II) may be prepared by subjecting a compound of general formula (IX) or a salt thereof to a reductive cyclization reaction:

wherein R is₁、R₂And, R₃As defined in claim 1, Hal is halogen (preferably bromine) and the compound of formula (IX) can be prepared by reaction of a compound of formula (X) with a compound of formula (XI):

wherein R is₁And Hal is as defined above,

wherein R is₂And R₃Is as defined above.

In the compounds of the formula Ia or Ib prepared, R in position 5 is preferred₁Is methyl or hydroxymethyl, R₂And R₃Is hydrogen, and R₄And R₅Are all isopropyl.

In a third aspect, the present invention provides novel compounds of formula (II), (IIIa), (IIIb), (IVa), (IVb), (Va), (Vb) and (IX) as described above, wherein R in position 5₁Is methyl or hydroxymethyl, R₂And R₃Is hydrogen and provides a compound of formula (IX) wherein R in position 5₁Is hydroxymethyl, R₂And R₃Is hydrogen, and halogen is Br, J or F.

Detailed Description

The basic idea of the invention is to enantioselectively reduce a compound of formula (II) to an enantiomerically enriched form of a compound of formula (IIIa) or (IIIb) and then to rearrange the compound of formula (IIIa) or (IIIb) to form the lactone (Va) or (Vb). The respective lactone enantiomers can then be further reacted to tolterodine by methods known per se in the art, for example as described in the above-mentioned US-A-5,382,600 and US-A-5,922,914.

The enantioselective reduction of the compound of formula (II) to the compound of formula (IIIa) or (IIIb) can be carried out in an organic solvent with a variety of reducing agents and the reaction conditions are those known per se in the art for the enantioselective reduction of carbonyl groups. Such methods are described, for example, in Houben-Weyl, Stereoselective Synthesis (Stereoselective Synthesis), ed: hunter Helmchen et al, Vol.7, Chapter 2.3, Thime, Stuttgart-New York 1996. Preferably, the reaction is carried out at about 0 ℃ to about room temperature. An exemplary process involves the use of chiral catalysts, such as commercially available (R) -or (S) -MeCBS (3, 3-diphenyl-1-methyltetrahydro-1H, 3H-pyrrolo- [1, 2-c ] [1.3.2] oxazaborole), borane complexes and bases. In the asymmetric borane reduction of compound (II), stereochemistry may be directed with the R or S enantiomer of the MeCBS oxazaborolidine catalyst. Similar substrate reductions are described, for example, in WO 97/17341. The enantioselectivity of asymmetric borane reduction is not very sensitive to the steric electronic effect.

The sigma-shift 1, 3-rearrangement (hydride transfer) of the compound (IIIa) or (IIIb) can be carried out by using a base (e.g., triethylamine) and a palladium catalyst (e.g., Pd (dppe) Cl) in an organic solvent₂([1, 2-bis (diphenylphosphino) ethane)]Palladium (II) chloride) treatment to form a compound of formula (IVa) or (IVb) (see, e.g., WO 97/17341 above). Alternatively, DABCO (1, 4-diazabicyclo [2.2.2] can be used in organic solvents]Octane) and a base (e.g., triethylamine) to effect the rearrangement (see example 1 below). The indanone (IVa) or (IVb) obtained is generally a highly crystalline solid, which makes it possible, if desired, to increase the enantiomeric purity by recrystallization from a suitable solvent (e.g.an enantiomeric excess (as defined below) of 99% or more can be obtained).

As is well known in the art, various oxidizing agents such as hydrogen peroxide or peroxy acids (e.g., 3-chloroperbenzoic acid) preferably effect bayer-verger oxidation of compounds (IVa) and (IVb) in the presence of an acid catalyst (e.g., p-toluenesulfonic acid (TsOH)). The reaction is preferably carried out in an organic solvent and, for example, at about 0 ℃ to about room temperature.

The purity of an enantiomer or the abundance of an enantiomer is generally expressed as "enantiomeric excess", abbreviated hereinafter as "ee", and is defined as (R-S)/(R + S), where R and S are the amounts of the R-and S-enantiomers, respectively. For the purposes of the present invention, the enantiomeric purity in the enantioselective processing step is generally at least about 50%, preferably at least about 85%.

Because tolterodine is an amine, it can form salts with organic and inorganic acids. Depending on the pharmaceutical dosage form, a pharmaceutically acceptable salt may be preferred over the corresponding free amine because the former produces a compound that is more water soluble and more crystalline. Exemplary pharmaceutically acceptable salts include acid-containing salts, wherein examples of the acids are methanesulfonic acid, hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, benzoic acid, citric acid, tartaric acid, fumaric acid, and maleic acid.

The invention will now be further illustrated by the following non-limiting examples.

In the examples:

TLC refers to thin layer chromatography.

MeCBS means 3, 3-diphenyl-l-1-methyltetrahydro-1H, 3H-pyrrolo- [1, 2-c ] [1.3.2] oxazaborole.

DABCO refers to 1, 4-diazabicyclo [2.2.2] octane.

ChiralCel OD-H (trade mark) refers to a chiral stationary phase for liquid chromatography, which consists of cellulose tris (3, 5-dimethylphenylcarbamate) on a silica gel substrate (Daicel Chemical Industries, Ltd).

mCPBA means 3-chloroperbenzoic acid

"ee" refers to enantiomeric excess as defined above.

Example 1:

1- (2-bromo-4-methylphenyl) -3-phenyl propenone

To a solution of 2-bromo-4-methylacetophenone (7.20g, 34.0mmol) and benzaldehyde (3.65g, 34.0mmol) in anhydrous methanol (50ml) was added freshly prepared sodium methoxide (35.7mmol) in anhydrous methanol (30ml) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 5 hours and allowed to warm to room temperature overnight. 10ml of HCl (10%) are slowly added and the mixture is almost evaporated to dryness under reduced pressure. The residue was suspended in saturated NaHCO₃(50ml) and extracted with 3X 50ml diethyl ether, washed with brine and MgSO₄And (5) drying. Purification was carried out by flash chromatography eluting with diethyl ether pentane 5: 95 to give 10.1g (95%) of the title compound. R_f0.66 (diethyl ether: pentane 20: 80).¹H NMRδ：2.25(s，3H)，6.96(d，J＝10.2Hz，1H)，7.15(d，J＝10.2Hz，1H)，7.05(dd，J＝7.6Hz，2.6Hz，1H)，7.24(m，3H)，7.34(m，2H)，7.40(m，3H).¹³C NMR δ：21.4，112.5，117.3，122.5，122.8，123.7，124.9，128.4，132.2，133.6，133.9，143.6，145.3，186.6。

5-methyl-3-phenylindan-1-ones

To anhydrous K₂CO₃(9.76g, 70.6mmol) suspension in anhydrous DMF (100ml) was added 1- (2-bromo-4-methylphenyl) -3-phenylpropenone (8.40g, 28.3mmol) and the mixture degassed with anhydrous argon for 15 min. Triphenylphosphine (0.73g, 2.83mmol) was added followed by PdCl₂(0.20g, 1.13 mmol). The mixture was heated at 80 ℃ until the NMR sample indicated disappearance of the starting material (5 hours). The mixture was reduced to half volume under reduced pressure and poured onto ice/water (200 ml). By CH₂Cl₂Extraction and subsequent purification by flash chromatography eluting with diethyl ether: pentane 5: 95 gave 4.2g (72%) of the title compound. R_f0.62 (diethyl ether: pentane 20: 80). IR (Net cm)^-1)：1704，1606，1355，1101，815，743。¹H NMR δ：2.40(s，3H)，5.99(s，1H)，7.11(d，J＝7.2Hz，1H)，7.18(s，1H)，7.43(d，J＝7.6Hz，1H)，7.53(m，3H)，7.66(m，2H)。¹³C NMRδ：22.1，122.7，122.9，123.5，127.4，128.6，128.9，129.2，129.9，130.3，133.2，143.7，144.4，162.4。MS(EI70 eV) m/z (relative intensity): 220(100) [ M⁺]，205(75)，191(51)，177(10)，165(15)。

5-methyl-3-phenyl- (S) -1H-inden-1-ol

The (R) -MeCBS catalyst (0.22ml, 1M, 0.22mmol) was mixed in 5ml of anhydrous THF and stirred at room temperature for 1 hour. After cooling to 0 ℃ 2.5ml of 2M BH in THF were added₃:Me₂S (4.99 mmol). A solution of 5-methyl-3-phenyl-indan-1-one (1.00g, 4.54mmol) in toluene (2ml) was added over a period of 2 hours via syringe pump. After the reaction, TLC was performed. After completion, methanol (0.6ml, 17mmol) was added at 0 ℃ and the mixture was evaporated to dryness. Flash chromatography eluting with ethyl acetate: pentane 10: 90 gave 0.96g (95%) of the title compound. R_f0.35 (ethyl acetate: pentane 20: 80) (ChiralCel OD-H)0.5 ml/min hexane/isopropanol: 95/5(S) -isomer 24.53 min, (R) -isomer 27.22 min, 93% ee.IR (neat cm)^-1)：3300，1605，1446，949，813。¹H NMRδ：1.40(s，1H)，2.40(s，3H)，5.27(d，J＝8Hz，1H)，6.43(d J＝2Hz，1H)，7.18(d，J＝8Hz，1H)，7.27(s，1H)，7.47(m，4H)，7.59(m，2H)。¹³C NMR. delta.: 21.6, 76.2, 121.6, 123.6, 126.9, 127.6, 128.2, 128.6, 134.1, 134.9, 138.2, 142.1, 143.7, 145.6. MS (EI70 eV) m/z (relative intensity): 220(100) [ M⁺]，207(71)，178(66)，144(42)，116(23)。

5-methyl-3- (S) -phenylindan-1-ones

5-methyl-3-phenyl- (S) -1H-inden-1-ol (750mg, 3.41mmol) and DABCO (190mg, 1.71mmol) were dissolved in dry THF: triethylamine 20: 1(15ml) and refluxed for 3 hours. The reaction mixture was evaporated to dryness. Flash chromatography eluting with ethyl acetate: pentane 5: 95 gave 690mg (92%) of the title compound. R_f0.62 (Ethyl acetate: pentane 20: 80) (ChiralCel OD-H)0.5 ml/min hexane/isopropanol: 95/5(S) -isomer 19.12 min, (R) -isomer 22.33 min, 89% ee. IR (Net cm)^-1)：3027，2361，1710，1605，1280，1238，1040。¹H NMRδ：2.39(s，3H)，2.69(dd，J＝3.0，19.2Hz，1H)，3.23(dd，J＝8.0，19.2Hz，1H)，4.53(q，J＝4Hz，1H)，7.07(s，1H)，7.14(d，J＝8.4Hz，1H)，7.15(s，1H)，7.26(m，2H)，7.33(m，2H)，7.72(d，J＝7.6Hz，1H)。¹³C NMR. delta.: 22.1, 44.3, 46.9, 123.2, 126.9, 127.0, 127.6, 128.9, 134.5, 143.8, 146.3, 158.4, 205.5. MS (EI70 eV) m/z (relative intensity): 220(100) [ M⁺]，207(55)，194(19)，178(60)，144(10)。

6-methyl-4- (S) -phenylchroman-2-ones

5-methyl-3- (S) -phenyl-indan-1-one (400mg, 1.8mmol) and mCPBA (98%, 485mg, 2.8mmol) were suspended in anhydrous CH at 0 deg.C₂Cl₂(6ml) and then suspended in TsOH: H₂0(20 mg). The reaction was maintained at 4 ℃ for 48 hours. The mixture was diluted with 10ml of CH₂Cl₂Diluted and saturated Na 2X 10ml₂SO₃Saturated NaHCO₃And a brine wash. Flash chromatography eluting with ethyl acetate: pentane 10: 90 gave 390mg (90%) of the title compound. R_f0.83 (ethyl acetate: pentane 20: 80) (ChiralCel OD-H)0.5 mL/min hexane/isopropanol 95/5(S) -isomer 15.18 min, (R) -isomer 17.42 min, 89% ee. IR (Net cm)^-1)：2900，2360，1769，1495，1208，1145。¹H NMRδ：2.28(s，3H)，3.05(m，1H)，4.32(t，J＝6.8Hz，1H)，6.98(s，1H)，7.04(d，J＝8.4Hz，1H)，7.11(dd，J＝2.0，8.4Hz，1H)，7.18(d，J＝8.4Hz，1H)，7.19(s，1H)，7.33(m，3H)¹³C NMR. delta.: 20.7, 37.1, 40.7, 116.8, 125.3, 127.5, 127.6, 128.6, 129.1, 129.3, 134.3, 140.5, 149.6, 167.8. MS (EI70 eV) m/z (relative intensity): 238(55) [ M ]⁺]，220(57)，195(100)，181(10)，165(12)，152(9)。

(R) -N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine (tolterodine)

Tolterodine may be prepared from the 6-methyl-4- (S) -phenyl chroman-2-one obtained above by the process steps corresponding to examples 3 and 4 of US 5,922,914 mentioned above, the entire disclosure of which is incorporated herein by reference, i.e. (i) reduction of the lactone 6-methyl-4- (S) -phenyl chroman-2-one with diisobutylaluminum hydride in toluene solution at-20 to-25 ℃ to give its corresponding hydroxy compound 6-methyl-4- (S) -phenyl-chroman-2-ol; (ii) the title compound (tolterodine) was obtained in the form of a substantially pure enantiomer by reductive amination of 6-methyl-4- (S) -phenyl-chroman-2-ol in methanol by reaction with diisopropylamine at 45-50psi pressure and 48 ℃ and hydrogenation with palladium on carbon, followed by filtration (solka floc).

Claims (11)

1. A process for the enantioselective preparation of a compound of the general formula (Ia) or (Ib):

wherein R is₁、R₂And R₃Independently of one another, hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulfamoyl or halogen, R₄And R₅Independently of one another are C_1-6-an alkyl group, the method comprising the steps of:

a) enantioselectively reducing the carbonyl function of the compound of formula (II),

wherein R is₁、R₂And R₃Is as defined above, to form an enantiomerically enriched compound of formula (IIIa) or (IIIb):

wherein R is₁、R₂And R₃Is as defined above;

b) subjecting the compound of formula (IIIa) or (IIIb) to sigma migratory rearrangement to form the corresponding enantiomerically enriched compound of formula (IVa) or (IVb):

wherein R is₁、R₂And R₃Is as defined above;

c) subjecting the compound of formula (IVa) or (IVb) to bayer-virger oxidation to form the corresponding enantiomerically enriched compound of formula (Va) or (Vb):

wherein R is₁、R₂And R₃Is as defined above;

d) converting a compound of formula (Va) or (Vb) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib); and

e) optionally converting the compound of formula (Ia) or (Ib) into a salt thereof.

2. The method of claim 1, wherein step d) comprises:

d1) reacting a compound of formula (Va) or (Vb) with an amine of general formula (VI),

wherein R is₄And R₅As defined in claim 1, to form a corresponding enantiomerically enriched compound of formula (VIIa) or (VIIb):

wherein R is₁、R₂、R₃、R₄And R₅Is as defined above; and

d2) reducing the carbonyl function of the compound of formula (VIIa) or (VIIb) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib).

3. The process according to claim 2, wherein steps d1) and d2) are carried out simultaneously in a one-step reaction.

4. The method of claim 1, wherein step d) comprises:

d 1') reducing the compound of formula (Va) or (Vb) to form the corresponding enantiomerically enriched hydroxy compound of formula (VIIIa) or (VIIIb):

wherein R is₁、R₂And R₃As defined in claim 1; and

d 2') reductively aminating the hydroxy compound of formula (VIIIa) or (VIIIb) with an amine of formula (VI) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib).

5. A process for the enantioselective preparation of a compound of the general formula (Ia) or (Ib):

wherein R is₁、R₂And R₃Independently of one another, hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulfamoyl or halogen, R₄And R₅Independently of one another are C_1-6-an alkyl group, the method comprising the steps of:

d) converting a compound of formula (Va) or (Vb) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib):

and

e) optionally converting the compound of formula (Ia) or (Ib) into a salt thereof.

6. The method of claim 5, wherein step d) comprises:

d1) reacting a compound of formula (Va) or (Vb) with an amine of general formula (VI),

wherein R is₄And R₅As defined in claim 1, to form a corresponding enantiomerically enriched compound of formula (VIIa) or (VIIb):

wherein R is₁、R₂、R₃、R₄And R₅Is as defined above; and

d2) reducing the carbonyl function of the compound of formula (VIIa) or (VIIb) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib).

7. The process according to claim 6, wherein steps d1) and d2) are carried out simultaneously in a one-step reaction.

8. The method of claim 5, wherein step d) comprises:

d 1') reducing the compound of formula (Va) or (Vb) to form the corresponding enantiomerically enriched hydroxy compound of formula (VIIIa) or (VIIIb):

wherein R is₁、R₂And R₃As defined in claim 1; and

d 2') reductively aminating the hydroxy compound of formula (VIIIa) or (VIIIb) with an amine of formula (VI) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib).

9. A method according to any one of claims 1 to 8, wherein R at position 5₁Is methyl or hydroxymethyl, R₂And R₃Is hydrogen, R₄And R₅Are all isopropyl.

10. A process according to any one of claims 1 to 4 and 5 to 9, wherein tolterodine is prepared.

11. The compound of formulae (IVa), (IVb), (Va) and (Vb) according to any one of claims 1 to 9, wherein R in position 5₁Is methyl or hydroxymethyl, R₂And R₃Is hydrogen.