TECHNICAL FIELD

[0001] The present invention relates to a novel process for the preparation of L-1 -pheny l-2-(pyrrolidin-1 -y l)propan-1 -ol.

BACKGROUND OF THE INVENTION

[0002] L-l-phenyl-2-(pyrrolidin-l-yl)propan-l-ol, also known as N-pyrrolidinyl norephedrine, I, is an extensively used chiral auxiliary. It has been used for enantioselective addition of dialkyl zinc to prochiral ketones. It is being used commercially as a chiral auxiliary for synthesis of anti HIV drug, Efavirenz.

[0003] N-pyrrolidinyl norephedrine has been prepared by alkylation of L-norephedrine as follows (Organic Synthesis Vol 77, pi2):

[0004] The above-mentioned process requires pure L-norephedrine as a starting material. This material is increasingly coming under narcotic controls the world over as a potential precursor of arcotic/psychotropic substances such as cathine and amphetamine. Hence there is a need to find alternative routes to prepare the title compound using starting materials that are not narcotic precursors and easily available.

SUMMARY OF THE PRESENT INVENTION

[0005] It is an object of the present invention to provide a process for preparation of N-pyrrolidinyl norephedrine without having to use L-norephedrine as a starting material. More particularly, the present invention relates to a process to prepare N-pyrrolidinyl norephedrine (I) using L-phenylacetylcarbinol as a starting material.

DETAILED DESCRIPTION OF THE INVENTION
[0006] L-norephedrine has been prepared from a chiral precursor, L-phenylacetylcarbinol, II (US 7414153, EP 1735266) as shown below:

[0007] Thus, L-phenylacetylcarbinol can be used as starting material for 2-(substituted amino)-1-phenyl-1-propanols through reductive amination. The present invention relates to a process to prepare N-pyrrolidinyl norephedrine (I) using L-phenylacetylcarbinol as a starting material. The process essentially involves reaction of L-phenylacetylcarbinol with a compound (III) of the general formula H2N-(CH2)4-X (III) under reductive amination conditions. The compound III can be with X equal to either -OH or -NH2. The product of reductive amination may be suitably treated to cyclize it to the target compound. The process is represented in Scheme I

[0008] In one aspect of this invention, 4-aminobutanol is used as a reductiveanimation agent. L-phenylacetylcarbinol is dissolved in a suitable solvent and reacted with 4-aminobutanol and hydrogen in the presence of a platinum catalyst. Next, the product of this reaction is isolated by filtration and evaporation of solvent. The product is N-(4-hydroxybutyl)-l-norephedrine and the diastereomeric purity of the said compound is about 93% erythro and 7% threo isomers. The product, if desired in a pure form, can be purified by salt formation with inorganic acids selected from a group comprising hydrochloric acid or sulphuric acid or organic acids selected from a group comprising oxalic acid, maleic acid, benzoic acid, acetic acid, whereby, the less soluble salt of the desired erythro isomer selectively precipitates. However, for conversion to N-pyrrolidinyl norephedrine, the crude product of hydrogenation can be directly used without any disadvantage.

[0009] The solvents that can be used for this reaction include toluene, benzene, C1-3 aliphatic alcohols or a mixture of any two thereof and ethyl acetate. Molar ratio of 4-aminobutanol to L-phenylacetylcarbinol is between the range of 1.0 and 1.3. Any further increase in the ratio does not increase the yield of the

product. The temperature of reaction can be between ambient and 100°C. Pressure of hydrogen of the reaction is between atmospheric and 15 kg/cm . The platinum catalyst is used in a ratio of 0.5 to 1.5% by weight of L-phenylacetylcarbinol

[0010] In a preferred embodiment of this invention, this reaction can be advantageously carried out using toluene or methanol or a mixture thereof as a solvent. A molar ratio of 4-aminobutanol to L-phenylacetylcarbinol of 1.05, temperature of reaction between 45-75°C, pressure of hydrogen between 3 and 7 kg/cm, catalyst quantity between 0.8 and 1.2% of the weight of L-phenylacetylcarbinol.

[0011] Still further, N-(4-hydroxybutyl)-l-norephedrine is dissolved in a suitable solvent, and next, treated with a suitable base and a condensing agent to convert into N-pyrrolidinyl norephedrine. The said product, N-pyrrolidinyl norephedrine is further isolated by steps comprising; a. dilution with water, b. addition of an acid to neutralize the base added, c. extraction with the solvent used for reaction and d. evaporation of the solvent. The crude product may then be purified via conversion to the hydrochloride salt and regeneration of the product by basification.

[0012] The solvents suitable for this reaction include but are not limited to tetrahydrofuran, 1,4-dioxane, chloroform, methylene chloride, toluene, benzene, ethylene dichloride. Base suitable for this reaction is selected from a group comprising triethylamine, pyridine, 4-dimethylaminepyridine, N-ethyldiisopropylamine. Temperature of reaction can be between -15° and 50°C. The condensing agent is selected from group comprising methanesulphonyl chloride, p-toluenesulfonyl chloride. The molar ratio of the condensing agent to N-(4-hydroxybutyl)-l-norephedrine is between 1.0 to 1.3. Any further increase in the ratio does not increase the yield of the product.

[0013] In another preferred embodiment of the present invention, the above process may be conducted advantageously using tetrahydrofuran as a solvent, triethylamine as a base, methanesulphonyl chloride as a condensing agent used in a molar ratio between 1.05 and 1.15 with respect to N-(4-hydroxybutyl)-l-norephedrine, at a temperature between -5 and 10°C.

[0014] In another aspect of the present invention, putrescine (1,4- diaminobutane) is used as reductive amination agent. L-phenylacetylcarbinol is dissolved in a suitable solvent and reacted with putrescine and hydrogen in the presence of a platinum catalyst. Next, the product of the reaction is isolated by filtration and evaporation of the solvent. The product is N-4-aminobutyl-l-norephedrine having a diastereomeric purity of greater than 99% erythro and less than 1% threo isomers. The product, if desired in a pure form, can further be purified by preparation of hydrochloride salt. However, for conversion to N-pyrrolidinyl norephedrine, the crude product of hydrogenation can be directly used without any disadvantage.

[0015] The solvents that can be used for this reaction include toluene, benzene, Q.3 aliphatic alcohols or a mixture of any two thereof. Molar ratio of putrescine to L-phenylacetylcarbinol is between 1.0 and 1.3. Any further increase in the ratio does not increase the yield of the product. The temperature of reaction can be between ambient and 100°C. Pressure of hydrogen of the reaction is between atmospheric and 15 kg/cm2. The platinum catalyst is used in a ratio of 0.5 to 1.5% by weight of L-phenylacetylcarbinol.

[0016] In a preferred embodiment of the invention, this reaction can be advantageously carried out using toluene or methanol or a mixture there of as a solvent, a molar ratio of putrescine to L-henylacetylcarbinol of 1.05, temperature of reaction between ambient to 60°C, pressure of hydrogen between 3 and 7 kg/cm, catalyst quantity between 0.8 and 1.2% of the weight of L-phenylacetylcarbinol.

[0017] For conversion of crude N-4-aminobutyl-l-norephedrine to N-pyrrolidinyl norephedrine, it is dissolved in a suitable solvent, treated with Raney Nickel catalyst and heated to temperature between 125 and 165°. The product, N-pyrrolidinyl norephedrine is isolated by dilution with water, addition of hydrochloric acid, separation of the solvent used for reaction and evaporation of the aqueous layer to give crude N-pyrrolidinyl norephedrine as hydrochloride salt. The crude product may be purified via recrystallization of the hydrochloride salt from water and regeneration of the base by basification.

[0018] In a preferred embodiment of the invention, this reaction can be advantageously carried out using a solvent having boiling point in the range of 125-165° or without any solvent. The quantity of Raney nickel catalyst is between 0.3 to 0.8 parts by weight of the starting material, preferably between 0.5-0.65 parts by weight.

[0019] The details of the invention, its objects, and its advantages are explained hereunder in great detail. The examples given below are merely illustrative and do not limit the scope of this invention and it would be obvious that any modifications or changes in the steps by those skilled in the art without departing from the scope of the invention shall be consequently encompassed within the ambit and spirit of this approach and scope thereof.

EXAMPLES
EXAMPLE 1

Preparation of l-phenyl-2-(4-hydroxybutyl)amino-propan-1 –ol

[0020] 12.5 g (140 mmol) 4-aminobutanol is reacted with 20 g (133 mmol) of L-phenylacetylcarbinol in 150 mL methanol under hydrogen atmosphere and 100 mg of a catalyst of platinum metal at 4-5 kg/cm2 pressure. After uptake of hydrogen ceased, the reaction mass is worked up by filtration of the catalyst and evaporation of methanol under vacuum. HPLC purity: erythro isomer: 92.7; threo isomer:7.5% !H NMR: 8 7.2-7.55 (m, 5 H), 5 5.13 (s, 1H), 5 3.3-3.5 (m, 3 H), 8 2.9-3.1 (m, 2H), 8 1.6-1.8 (m, 2H), 8 1.4-1.55 (m,2H), 8 0.85-0.95 d, 3H).

EXAMPLE 2

Preparation of 1 -phenyl-2- (pyrrolidin-1 -yljpropan- l-ol

[0021] The product (l-phenyl-2-(4-hydroxybutyl)amino-propan-l-ol) thus obtained is next dissolved in methylene chloride and then treated with methanesulphonyl chloride in the presence of triethylamine at 0-5°C for 2 hours. Washing the reaction mass with water and saturated brine followed by concentration of methylene chloride in vacuo isolates the product. The residue is neutralized with dilute hydrochloric acid, decolourized with activated carbon, concentrated to dryness, suspended in acetone and filtered. The product is crude hydrochloride salt of l-phenyl-2-(pyrrolidin-l-yl)propan-l-ol. It is then dissolved in water and treated with sodium hydroxide to precipitate l-phenyl-2-(pyrrolidin-l-yl)propan-l-ol. It is filtered, washed with water and dried in vacuum. Analytical data:

[0022] Melting range: 41-44°, aD20 : -9.48° (c, 5% in 1 N HC1). [required for pure (lR,2S)-l-phenyl-2-(pyrrolidin-l-yl)propan-l-ol : -13.5° to -15.5° c, 5% in 1 N HC1], chiral HPLC purity: (1R,2S) isomer: 82 %, (1S,2R) isomer: 18 %.

EXAMPLE 3

Preparation of 1 -phenyl-2-(4-aminobutyl)amino-propan-l-ol dihydrochloride

[0023] PAC (100 g, 1 eq.) in methanol (70ml.), 0.8 g of platinum catalyst and putrescine base (58.66 g, leq.) is charged to the autoclave. The reaction mixture is hydrogenated at 5 kg/cm pressure for 1.5 hrs. After hydrogen uptake is ceased, the reaction is further worked up by filtration of the catalyst and evaporation of the solvent. Next, the product is treated with hydrochloric acid to give hydrochloride salt. Recrystallization from isopropanol gives l-phenyl-2-(4-aminobutyl)amino-propan-l-ol dihydrochloride, mp 170.2-171.5°C, specific optical rotation: -16.06° (1% solution in water), 1HNMR (DMSO-d6): δ 8.95(s, 2H), 5 8.1 (s, 3H), 8 7.45-7.25 (m, 5H), 8 6.1 (d,lH), 8 5.2 (s, 1H), 8 3.3 (s, 1H), 8 3.1 (s, 2H), 8 2.8 (S,2h), 8 1.8 (m, 2H), 8 1.7 (m,2H), 8 0.9 (d, 3H). HPLC purity: erythro isomer 99%, threo isomer 1%.

EXAMPLE 4
Preparation of l-phenyl-2-(4-aminobutyl)amino-propan-l-ol base
[0024] l-phenyl-2-(4-aminobutyl)amino-propan-l-ol dihydrochloride (35 g) in water (50ml) is mixed with sodium hydroxide solution (35%) till basic, followed by addition of toluene. Separation of toluene layer and concentration in vacuo gives l-phenyl-2-(4-aminobutyl)amino-propan-l-ol base. Specific optical
rotation: -18.82°(1 % in 1 N HC1).

EXAMPLE 5
Preparation of 1 -phenyl-2- (pyrrolidin-1 -yl)propan- l-ol
[0025] l-phenyl-2-(4-aminobutyl)amino-propan-l-ol (5 g) is mixed with Raney Nickel catalyst (3.2 g). The reaction mixture is heated under stirring to 150-160 °C and maintained at 150-160 °C for 2 hrs. After the completion of the reaction, filtration of the catalyst and the usual work up of the reaction mixture
gives crude l-phenyl-2-(pyrrolidin-l-yl)propan-l-ol as hydrochloride salt. Recrystallization of the crude compound gives pure l-phenyl-2-(pyrrolidin-l- yl)propan-l-ol hydrochloride.

Claims:
We claim:

1. A process of preparing a compound of structure (I) l-l-phenyl-2-(pyrrolidin-1 -yl)propan-1 -ol comprising

i) reacting L-phenylacetylcarbinol with a reductive amination agent compound of the general formula H2N-(CH2)4-X, wherein, X is either –OH or -NH2 dissolved in a solvent and hydrogen in the presence of a catalyst;
and

ii) treating the product obtained by step (i) suitably to cyclize it to yield 1-1 -phenyl-2-(pyrrolidin-1 -y l)propan-1 -ol.

2. The process as mentioned in claim 1 wherein the reductive amination agent compound used for reaction with L-phenylacetylcarbinol comprises either 4-aminobutanol or 1,4-diaminobutane (putrescine)

3. The process as mentioned in step (i) of claim 1 wherein the solvent used comprises toluene, benzene or a Cj.3 aliphatic alcohol, ethyl acetate or a mixture thereof.

4. The process as mentioned in step (i) of claim 1 wherein the hydrogen pressure is between atmospheric pressure and 15 kg/cm .

5. The process as mentioned in step (i) of claim 1 wherein the temperature of the reaction is between ambient and 100°C.

6. The process as mentioned in step (i) of claim 1 wherein the catalyst is a platinum catalyst which is between 0.5 and 1.5 % of the weight of L-phenylacetylcarbinol.

7. The process as mentioned in step (i) of claim 1 wherein the molar ratio of reductive amination agent compound to L-phenylacetylcarbinol is between 1.0 and 1.3.

8. The process as mentioned in step (i) of claim 1 wherein the product of the hydrogenation step is dissolved in a solvent and treated with a base and condensing agent.

9. The reductive amination agent as mentioned in claim 7 is 4-aminobutanol.

10. The solvent as mentioned in claim 8 is selected from a group comprising tetrahydrofuran, 1,4-dioxane, chloroform, methylene chloride, toluene, benzene, ethylene dichloride.

10. The process as mentioned in claim 8 wherein the base used is selected from the group comprising triethylamine, pyridine, 4-dimethylaminepyridine, N-ethyldiisopropylamine.

11. The process as mentioned in claim 8 wherein the molar ratio of the condensing agent to the product of hydrogenation step is between 1.0 to 1.3.

12. The process as mentioned in claim 8 wherein the temperature of the reaction is between -15° and 50°C.

13. The process as mentioned in claim 1 wherein the reductive amination agent is 1,4-diaminobutane and wherein the condensing agent is Raney Nickel.

14. The process as mentioned in claim 13 wherein the temperature of the reaction is between 125° and 165°C.

15. The process as mentioned in claim 13 wherein the quantity of the Raney Nickel catalyst used is between 0.3 to 0.8 parts by weight of the starting material (N-4-aminobutyl-l-norephedrine).