WO2000050379A1

WO2000050379A1 - Process for the preparation of (1r, 2s, 4r) -(-) -2 - (2 -dimethylaminoethoxy) -2 -phenyl -1,7,7 - trimethylbicyclo [2.2.1] heptane

Info

Publication number: WO2000050379A1
Application number: PCT/HU2000/000014
Authority: WO
Inventors: Gyula Simig; Tibor Mezei; Lívia GREGORNÉ BOROS; Endréné FLÓRIÁN; Márta PORCS-MAKKAY; Gyula LUKÁCS; Sándorné CSEH
Original assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Current assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Priority date: 1999-02-24
Filing date: 2000-02-23
Publication date: 2000-08-31
Anticipated expiration: 2001-08-24
Also published as: AU3182300A; HUP9900445A2; HU9900445D0

Abstract

The invention relates to a process for the preparation of (1R,2S,4R) -(-) -2- (2-dimethylaminoethoxy) -2 -phenyl -1,7,7- trimethylbicyclo [2.2.1] heptane of Formula (I) and pharmaceutically acceptable acid addition salts thereof starting from (1R,2S,4R) -(-) -2- phenyl -1,7,7 - trimethylbicyclo [2.2.1] heptane -2-ol of Formula (III) and optionally converting (1R,2S,4R)-(-)-2- (2-dimethylaminoethoxy) -2-phenyl-1,7,7- Mtrimethylbicyclo [2.2.1] heptane into a salt thereof, which comprises reacting an alkali salt of (1R,2S,4R)-(-) -2-phenyl-1,7,7- trimethylbicyclo [2.2.1] heptane-2-ol of Formula (III) with a 2-halo-N,N- dimethyl-acetamide of general Formula (IV) (wherein X stands for halogen) and reducing the (1R,2S,4R)-(-)-N, N-dimethyl- (2-phenyl-1,7, 7-trimethylbicyclo [2.2.1] hept-2-yl) -oxy-acetamide of Formula (V) thus obtained. The compound of Formula (I) is a known anxiolytic pharmaceutical active ingredient. The process of the invention is readily feasible on industrial scale too, can be carried out through a crystalline new last intermediate which can be easily purified and provided a highly pure end product with excellent yields.

Description

Process for the preparation of (1R,2S,4R)-(-)-2-(2-

-dimethylaminoethoxy)-2-phenvM,7,7-trimethyl-

-bicyclor2.2.nheptane

Field of the invention

The invention relates to a process for the preparation of (1 R,2S,4R)-(-)-2-(2-dimethy!aminoethoxy)-2-phenyl-1 ,7,7- -trimethylbicyclo[2.2.1]heptane and pharmaceutically acceptable acid addition salts thereof.

(1 R,2S,4R)-(-)-2-(2-dimethyiaminoethoxy)-2-phenyl- -1 ,7,7-trimethylbicyclo[2.2.1]heptane of the Formula

and pharmaceutically acceptable acid addition salts thereof - particularly the fumarate - is a known anxiolytic active ingredient (HU-179,164). The INN of the fumarate (1 :1) of the compound of the Formula I is deramciciane. Technical background

The compound of the Formula I falls under the scope of the Formula I of HU-179,164. According to the general disclosure of said patent specification the compound of the Formula I is prepared by reacting camphor with the corresponding organic metal compound, hydrolyzing the adduct thus obtained and introducing the basic sidechain by etherification of the hydroxy group of the compound thus obtained. As organic metal compound a Grignard compound or an organic alkali compound - preferably lithium or sodium compound - can be used. The preparation of the compound of the Formula I is disclosed in none of the examples of HU-179,164. Following the general disclosure the compound of the Formula I cannot be prepared in a purity which meets the requirements of Pharmacopoeia or only with considerable losses.

In HU-212,574 an improved process for the preparation of the compound of the Formula I is disclosed. According to said process camphor [D-(+)-1,7,7-trimethylbicyclo[2.2.1]heptane-2- -one] of the Formula

is used as starting material. The essence of the process is that the utilization of camphor is improved by several-fold recirculation. The camphor of the Formula II is reacted with a Grignard compound prepared from bromo benzene and metallic magnesium. The adduct thus obtained is hydrolyzed and the solvent is removed. The residual (1 R,2S,4R)-(-)-2- -phenyl-1 ,7,7-trimethylbicyclo[2.2.1 ]heptane-2-ol of the Formula

is reacted with 2-(dimethylamino)-ethyl chloride without further purification. After the end of the reaction the (1 R,2S,4R)- -(-)-2-(2-dimethylaminoethoxy)-2-phenyl-1 ,7,7-trimethyl- bicyclo[2.2.1]heptane base of the Formula I is isolated by extracting the reaction mixture with tartaric acid, making the tartaric acid extract alkaline, extracting with an organic solvent and evaporating the extract. The base of the Formula I can be converted into a pharmaceutically acceptable acid addition salt, if desired. The residue obtained after extraction with tartaric acid is made free of solvent, the residue is enriched by addition of camphor of the Formula II and subjected to etherification. This procedure is repeated several times.

The drawback of this process is that it is complicated and a major part of the contaminations is removed only in the salt formation step.

It is the object of the invention to elaborate a new and improved process for the preparation of highly pure compound of the Formula I which process is easily feasible on industrial scale too and provides good yields.

The above object is reached with the aid of the process of the present invention by using a new intermediate product. Summary of the invention

According to the present invention there is provided a process for the preparation of (1 R,2S,4R)-(-)-2-(2-dimethyl- aminoethoxy)-2-phenyl-1 ,7,7-trimethyl-bicyclo[2.2.1]heptane of the Formula I and pharmaceutically acceptable acid addition salts thereof starting from (1 R,2S,4R)-(-)-2-phenyl-1 ,7,7- -trimethylbicyclo[2.2.1]heptane-2-ol of the Formula III and optionally converting (1 R,2S,4R)-(-)-2-(2-dimethylaminoethoxy)- -2-phenyl-1 ,7,7-trimethylbicyclo[2.2.1]heptane into a salt thereof, which comprises reacting an alkali salt of (1 R,2S,4R)-(-)-2-phenyl-1 ,7,7-trimethylbicyclo[2.2.1]heptane-2- -ol of the Formula III with a 2-halo-N,N-dimethyl-acetamide of the general Formula

(wherein X stands for halogen) and reducing the (1 R,2S,4R)- -(-)-N,N-dimethyl-(2-phenyl-1 ,7,7-trimethylbicyclo[2.2.1]hept-2- -yl)-oxy-acetamide of the Formula

thus obtained. The present invention is based on the recognition that the new compound of the Formula V, never described in prior art, can be readily crystallized and can be easily purified. The contaminations and by-products formed in the course of the synthesis can be removed by crystallization of the compound of the Formula V to a very great extent and due to this fact a highly pure compound is used as last intermediate in the synthesis of the desired compound of the Formula I. Details of the invention

According to the first step of the process of the present invention an alkali salt of the compound of the Formula III is reacted with a 2-halogeno-N,N-dimethyl-acetamide of the general Formula IV. The compound of the Formula III is known from prior art [Deno et al. J. Amer. Chem. Soc, 77, 3044 (1955)]. The starting material of the Formula III is converted into an alkali salt, preferably the sodium or potassium salt, particularly advantageously the sodium salt. The reaction is carried out by using an alkali hydride or alkali amide, such as sodium hydride, potassium hydride, sodium amide or potassium amide. An ether (e.g. diethyl ether, tetrahydrofurane, dioxane etc.) or an aromatic hydrocarbon (e.g. benzene, toluene, xylene) may serve as reaction medium. One may work preferably in tetrahydrofurane as medium. The alkali salt of the compound of the Formula III can be prepared at 10-50°C, preferably at room temperature.

The alkali salt formed is reacted with a compound of the general Formula IV. It is preferred to use 2-chloro-N,N- -dimethyl-acetamide, i.e. a compound of the general Formula IV, wherein X stands for chlorine. According to a preferred form of realization of the process of the present invention the reaction between the alkali salt of the compound of the Formula III and the 2-halo-N.N-dimethyl-acetamide of the general Formula IV is carried out without isolating the in situ formed alkali salt, i.e. in the reaction mixture obtained by the formation of said alkali salt. Accordingly the reaction medium used by the reaction between the alkali salt of the compound of the Formula III and the compound of the general Formula IV is the same as used in the alkali salt formation. One may preferably work in tetrahydrofurane as medium. The reaction between the alkali salt of the compound of the Formula III and the 2-halo-N,N-dimethyl-acetamide of the general Formula IV can be carried out at 10-50°C, preferably at room temperature. The reaction takes place within some hours, the advantageous reaction time being 1-3 hours.

The formed compound of the Formula V is isolated from the reaction mixture by extraction (preferably with ethyl acetate) and evaporation of the extract. The compound of the Formula V is purified by crystallization. Said crystallization can be carried out from a hydrocarbon (e.g. pentane, hexane, heptane, cyclohexane etc.) or a mixture thereof formed with ethyl acetate. One may work preferably by crystallizing the compound of the Formula V from a mixture of hexane and ethyl acetate. The crystalline compound of the Formula V obtained is of high purity, contains only small amounts of contaminations and is suitable for the preparation of the end product of the Formula I meeting the up-to-date requirements of Pharmacopoeia.

The compound of the Formula V thus obtained is reduced into the desired compound of the Formula I. Reduction can be carried out with any metal hydride suitable for the reduction of acid amides, or a complex of a Lewis acid formed with a metal hydride or a borohydride/dimethyl sulfide complex. It is preferred to use lithium aluminium hydride or a borohydride/dimethyl sulfide complex as reducing agent. Reduction can be performed in an ether type solvent as reaction medium (e.g. tetrahydrofurane, dimethyl ether, diisopropyl ether etc.). One may work preferably in tetrahydrofurane as medium. Reduction can be carried out under heating, advantageously at the boiling point of the reaction mixture. The reaction is complete within some hours, the preferred reaction time being 1-3 hours.

The product can be isolated from the reaction mixture by extraction with an organic solvent (preferably ethyl acetate), drying and evaporating the extract. The crude product of the Formula I obtained after reduction is of high purity, the contamination content determined by HPLC being below 1 %.

The compound of the Formula I can be converted, if desired, into a pharmaceutically acceptable salt by known methods. For salt formation inorganic acids (e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid) or organic acids (e.g. acetic acid, tartaric acid, succinic acid, lactic acid, malic acid, maleic acid, fumaric acid etc.) can be used. It is preferred to prepare the fumarate salt. The fumarate can be formed in a known manner by adding to the solution of the base of the Formula I and a suitable inert organic solvent a solution of fumaric acid formed with a suitable organic solvent. It is preferred to dissolve the base of the Formula I and fumaric acid in the same solvent. As reaction medium preferably lower alkanols, particularly ethanol can be used.

The (1 R,2S,4R)-(-)-N,N-dimethyl-(2-phenyl-1 ,7,7-trimethyl- bicyclo[2.2.1]hept-2-yl)-oxy-acetamide of the Formula V is a new compound, never described in prior art.

According to a further aspect of the present invention there is provided (1R,2S.4R)-(-)-N,N-dimethyl-(2-ρhenyl-1 ,7,7- -trimethylbicyclo[2.2.1]hept-2-yl)-oxy-acetamide of the Formula V.

The advantages of the process of the present invention are as follows:

The process

• is readily feasible on industrial scale too;

• is carried out via a readily crystallizable crystalline last intermediate compound;

• gives with excellent yield highly pure compound of the Formula I which meets the requirements of Pharmacopoeia.

Further details of the present invention are to be found in the Examples, without limiting the scope of protection to said Examples. Example 1

(1 R.2S,4R)-(-)-N. N-dimethyl-(2-phenyl-1 ,7.7-trimethyl- -bicvclo[2.2.1lhept-2-yl)-oxy-acetamide

5.28 g (0.11 mole) of a 50 % sodium hydride dispersion are suspended in 100 ml of anhydrous tetrahydrofurane, whereupon to the suspension thus obtained a solution of 20.5 g (0.089 mole) of (1 R,2S,4R)-(-)-2-phenyl-1 ,7,7-trimethyl- -bicyclo[2.2.1]heptane-2-ol and 50 ml of anhydrous tetrahydrofurane is added dropwise under nitrogen or argon. The mixture is heated to boiling for an hour, whereupon it is cooled to 25°C and a solution of 14.0 g (0.12 mole) of 2-chloro-N,N-dimethyl- -acetamide and 50 ml of anhydrous tetrahydrofurane is added. The reaction mixture is stirred at 25°C for half an hour, whereupon 250 ml of water are added. The product is extracted with ethyl acetate, filtered over silica and evaporated. The residue is crystallized from a 4:1 mixture of hexane and ethyl acetate. Thus 27.4 g of (1 R,2S,4R)-(-)-N,N- -dimethyl-(2-phenyl-1 ,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-oxy- -acetamide are obtained in the form of faint yellow crystals. Yield 85.0 %, mp.: 77-78°C. [α]²⁰ = -64.9° (c=1 , chloroform).

D

Analysis: for the Formula C₂₀H₂gNO (315.5)

C H N caic: 75.37 %, 9.17 %, 4.39 %; found: 75.25 %, 9.23 %, 4.42 %.

¹H-NMR (CDCI₃, 400 MHz): δ 7.56-7.50 (1H, m), 7.7.40-7.20 (4H, m), 3.68 (1 H, d, J=13.2 Hz), 3.62 (1 H, d, J=13.2 Hz), 3.00 (3H, broad s), 2.93 (3H, broad s), 2.30 (1H, dt, J=13.8 Hz, J=4.1 Hz), 2.11 (1 H, d, =13.8 Hz), 1.90 (1 H, t, =13.8 Hz), 1.75-1.65 (1H, m), 1.25-1.16 (1 H, m), 1.19 (3H, s), 1.14-1.09 (1 H, m), 0.96 (3H, s), 0.90 (3H, s), 0.72-0.65 (1 H, m). Example 2

(1 R,2S,4R)-(-)-N. N-dimethyl-(2-phenyl-1 ,7.7-trimethyl- bicyclof2.2.11hept-2-yl)-oxy-acetamide

One proceeds as described in Example 1 except that the reaction is carried out in diethyl ether in the place of tetrahydrofurane.

Thus 28.3 g of (1 R,2S,4R)-(-)-N,N-dimethyl-(2-phenyl- -1 ,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-oxy-acetamide are obtained in the form of faint yellow crystals, yield 88.0 %, mp.: 77°C. Example 3

(1 R,2S,4RH-)-2-(2-dimethylaminoethoxy)-2-phenyl-1.7,7- -trimethylbicyclof2.2.11heptane-2-(E)-butenedioate (1 :1)

To a solution of 31.55 g (0.1 mole) of (1 R,2S,4R)-(-)- -N,N-dimethyl-(2-phenyl-1 ,7,7-trimethylbicycio[2.2.1]hept-2-yl)- -oxy-acetamide prepared according to Example 1 and 200 ml of anhydrous tetrahydrofurane 3.8 g (0.1 mole) of lithium aluminium hydride are added at 25°C under argon. The reaction mixture is heated to boiling for 2 hours, cooled to room temperature and 150 ml of a saturated aqueous ammonium chloride solution are added dropwise. The product is extracted with ethyl acetate, dried and evaporated to dryness in vacuo. Salt formation

On evaporation 26.7 g (88 mmol) of a faint yellow oil are obtained, which is (1 R,2S,4R)-(-)-2-(2-dimethyl- aminoethoxy)-2-phenyl-1 ,7,7-trimethylbicyclo[2.2.1]heptane having a purity of 99.0 % by weight according to HPLC. This oil is taken up in 250 ml of ethanol, whereupon a solution of 10.3 g (88 millimoles) of fumaric acid and 120 ml of hot ethanol is added at the boiling point. The crystals are filtered after cooling to 0°C and washed with ethanol. Thus in the form of faint yellow crystals 36.0 g of (1 R,2S,4R)-(-)-2-(2-dimethylaminoethoxy)-2-phenyl- -1 ,7,7-trimethylbicyclo[2.2.1]heptane-2-(E)-butenedioate (1 :1) are obtained. Yield 97.5 %, mp.: 216-219°C. Analysis: for the Formula C₂₀H₃₁NO.C H₄O (417.55)

C H N calc: 69.03 %, 8.45 %, 3.35 %; found: 69.08 %, 8.40 %, 3.37 %.

[_α]²⁰ = -46.2° (c=1 , ethanol).

D

Example 4

(1 R,2S,4R)-(-)-2-(2-dimethylaminoethoxy)-2-phenyl-1.7.7- -thmethylbicvclof2.2.nheptane-2-(E)-butenedioate (1 :1)

To a solution of 3.15 g (10 mmol) of (1R,2S,4R)-(-)- -N,N-dimethyl-(2-phenyl-1 ,7,7-trimethylbicyclo[2.2.1]hept-2-yl)- -oxy-acetamide prepared according to Example 1 and 40 ml of anhydrous tetrahydrofurane a solution of 3.0 ml (30 millimoles) of 10 N borane/dimethyl sulfide (ALDRICH 17.982-5) is added dropwise at 10°C under nitrogen or argon. The reaction mixture is heated to boiling for 3 hours, cooled to 25°C, at this temperature 40 ml of a saturated ammonium chloride solution are added, the mixture is stirred at 40-50°C for 5 hours and the reaction mixture is made alkaline to pH 10. The product is extracted with ethyl acetate, the extract is dried and evaporated to dryness in vacuo. Salt formation

On evaporation 2.27 g (7.54 millimoles) of a faint yellow oil are obtained, yield 75.0 %. According to HPLC this oil is (1 R,2S,4R)-(-)-2-(2-dimethylaminoethoxy)-2-phenyl-1 ,7,7- -trimethylbicyclo[2.2.1]heptane of a purity of 99.5 %. The oil thus obtained is taken up in 30 ml of ethanol and at the boiling point a solution of 0.87 g (7.54 millimoles) of fumaric acid and 10 mi of hot ethanol is added. The crystals are filtered at 0°C, and washed with ethanol. Thus 3.02 g of crystalline (1 R,2S,4R)-(-)-2-(2-dimethylaminoethoxy)-2-phenyl-1 ,7,7- -trimethylbicyclo[2.2.1]heptane-2-(E)-butenedioate (1 :1) are obtained. Yield 96.3 %, mp.: 215°C. [ ]²⁰ = -46.2° (c=1 , ethanol).

D

Content measured by HPLC: 99.5 %.

Claims

What we claim is,

1. Process for the preparation of (1R,2S,4R)-(-)-2- -(2-dimethylaminoethoxy)-2-phenyl-1,7,7-trimethyl- bicyclo[2.2.1]heptane of the Formula

and pharmaceutically acceptable acid addition salts thereof starting from (1R,2S,4R)-(-)-2-phenyl-1 -trimethyl- bicyclop^.llheptane^-ol of the Formula

and optionally converting (1 R,2S,4R)-(-)-2-(2-dimethylaminoethoxy)- -2-phenyl-1,7,7-trimethylbicyclo[2.2.1]heptane into a salt thereof, which comprises reacting an alkali salt of (1R,2S,4R)-(-)-2-phenyl-1,7,7-trimethylbicyclo[2.2.1]heptane- -2-ol of the Formula III with a 2-halo-N,N-dimethyl-acetamide of the general Formula o

X.

^'N IV

(wherein X stands for halogen) and reducing the (1R,2S,4R)- -(-)-N,N-dimethyl-(2-phenyl-1,7,7-trimethylbicyclo[2.2.1]hept-2- -yl)-oxy-acetamide of the Formula

thus obtained.

2. Process according to Claim 1 which comprises using as starting material 2-chloro-N,N- -dimethyl-acetamide of the general Formula IV, wherein X stands for chlorine.

3. Process according to Claim 1 or 2 which comprises using as starting material the sodium salt of the compound of the Formula III.

4. Process according to Claim 3 which comprises preparing the sodium salt of the compound of the Formula III by reacting (1R,2S,4R)-(-)-2-phenyl-1,7,7- -thmethylbicyclo[2.2.1]heptane-2-ol with an alkali hydride or amide.

5. Process according to Claim 4 which comprises using sodium hydride.

6. Process according to Claim 1 which comprises carrying out the reaction between the alkali salt of the compound of the Formula III and the compound of the general Formula IV in an inert solvent.

7. Process according to Claim 6 which comprises using as reaction medium an ether or an aromatic hydrocarbon.

8. Process according to Claim 7 which comprises using tetrahydrofurane as reaction medium.

9. Process according to any of Claims 6-8 which comprises carrying out the reaction between an alkali salt of the compound of the Formula III and the compound of the general Formula IV at 10-50°C, preferably at room temperature.

10. Process according to any of Claims 1-9 which comprises reducing the compound of the Formula V with a metal hydride, or a complex of a metal hydride formed with a Lewis acid, or a borohydride/dimethyl sulfide complex.

11. Process according to Claim 10 which comprises using lithium aluminium hydride as reducing agent.

12. Process according to Claim 10 which comprises using as reducing agent a borane/dimethyl sulfide complex.

13. Process according to any of Claims 10-12 which comprises carrying out reduction in an ether type solvent.

14. Process according to Claim 13 which comprises carrying out reduction in tetrahydrofurane.

15. Process according to any of Claims 10-14 which comprises carrying out reduction under heating, preferably at the boiling point of the reaction mixture.

16. Process according to any of the preceding Claims which comprises subjecting the compound of the Formula V obtained by reduction to crystallization.

17. Compound of the Formula I whenever prepared by the process according to Claim 1.

18. (1 R,2S,4R)-(-)-N,N-dimethyl-(2-phenyl-1 ,7,7- -trimethylbicyclo[2.2.1]hept-2-yl)-oxy-acetamide of the Formula V.