WO2017033134A1

WO2017033134A1 - Enzymatic process for the for preparation of (r)-1-(1-naphthyl) ethylamine, an intermediate of cinacalcet hydrochloride

Info

Publication number: WO2017033134A1
Application number: PCT/IB2016/055047
Authority: WO
Inventors: Sureshbabu Chillara; Amol Gulab KHATIK; Mofazzal Husain
Original assignee: Lupin Limited
Priority date: 2015-08-26
Filing date: 2016-08-24
Publication date: 2017-03-02

Abstract

The present invention provides a process for the preparation of enantiomerically pure (R)- 1-(1-naphthyl)ethylamine of formula (IIa) by treating 1-acetylnaphthalene of formula (I) with R-selective transaminase enzyme in presence of amino donor. The (R)-1-(1-naphthyl)ethylamine of formula (IIa) thus obtained is further converted to cinacalcet hydrochloride of formula (III).

Description

ENZYMATIC PROCESS FOR THE FOR PREPARATION OF

(R)-l-(l-NAPHTHYL) ETHYLAMINE, AN INTERMEDIATE OF CINACALCET

HYDROCHLORIDE

FIELD OF INVENTION The present invention provides novel process for preparation of enantiomerically pure (R)-1-(1-Naphthyl)ethylamine of formula (Ila) by reacting 1-Acetylnaphthalene of formula (I) with transaminase enzyme and its conversion to Cinacalcet hydrochloride of formula (III).

BACKGROUND OF THE INVENTION

Cinacalcet hydrochloride (III) is chemically known as N-[l-(R)-(-)-(l-naphthyl)ethyl]-3- [3-(trifluoromethyl)phenyl]-l-aminopropane hydrochloride known to be useful for the treatment of hyperparathyroidism and the preservation of bone density in patients with kidney failure or hypercalcemia due to cancer.

Cinacalcet hydrochloride is an oral calcimimetic drug. In the United States, it is marketed under the name Sensipar® and, in Europe, it is marketed under the name Mimpara® and Parareg®.

Enantiomerically pure chiral amine plays an important role in the pharmaceutical and chemical industry. Enantiomerically pure chiral amines in general are frequently used as a resolving agents or intermediates or synthons for the preparation of various physiologically, for instance pharmaceutically active substances. In a great number of the various applications of enantiomerically pure chiral amines, only one particular optically active form, either the (R) or the (S) enantiomer has the desired physiological activity. Thus, there is a clear need to provide processes for the preparation of chiral amines in an optically active form.

(R)-l-(l-naphthyl)ethylamine of formula (Ila) is used for the preparation of cinacalcet hydrochloride.

(Ila)

Prior art includes various synthetic methods for the preparation of (R)-l-(l- naphthyl)ethylamine of formula (Ila).

WO 2001012574 Al discloses preparation of optically active amine by reacting 1- acetylnaphthylene with hydroxylamine hydrochloride to furnish oxime, which was further treated with chlorodiphenylphosphme to provide imine derivative, which was subjected to asymmetric transfer hydrogenation catalyzed by Rh complex, followed by treatment of the obtained protected amine with hydrogen chloride gas in ethanol as shown in the scheme 1 :

Chiral amine

Scheme 1

WO 2004110976 A2 discloses preparation of optically active amine from the corresponding aldehyde by asymmetric synthesis comprising asymmetrically reducing corresponding aldehyde compound using rhodium complex and chiral ligand and then reacting with ammonia as shown in scheme 2.

L = Leaving gropup Chiral amine

Scheme 2

WO 2008058235 A2 discloses preparation of optically active amine from the corresponding aldehyde from the corresponding aldehyde by treating the aldehyde compound with a base (ammonium formate) in solvent to form racemic amine which on resolution gives optically active amine as shown in scheme 3.

Kacemic Chiral amine amine

Scheme 3

CN 101407465 B discloses preparing optical pure amine by using chiral aspartic acid as chiral resolving agent with the formation of diastereomeric salts and separating desired optically pure amine difference in their solubility. The drawbacks associated with the prior art synthetic methods are use of expensive ruthenium, iridium, or rhodium complexes and to show their content in final active pharmaceutical ingredient (API) is within the acceptable limits; high cost of asymmetric synthesis; difficulty to obtain a high optical purity of the product; poor yields (lack of diastereo- and enantioselectivity); cost, availability and difficulty of recovering these chiral resolving agents; cost and recyclability of hydrogenation catalyst.

In the view of the mentioned drawbacks in the prior art, there is an ongoing need to develop a process for the preparation of enantiomerically pure (R)-l-(l- naphthyl)ethylamine of formula (Ila) that bypasses the above limitations and is more efficient in terms of yield and resolution and at the same time is cost-effective for which an enzymatic approach would be the answer to the above mentioned problems.

The present invention uses transaminase enzyme to obtain optically active chiral amine. Depending on the enantio-preference of the selective transaminase used, an optically active chiral amine is obtained. For instance the R-selective transaminase enzyme herein is capable of catalyzing the transfer of an amino group from an amino donor to a keto substrate, thereby forming R-selective chiral amine. Eventually, the S-selective transaminase enzyme catalyses the transfer of an amino group from an amino donor to a keto substrate, thereby forming S-selective chiral amine. SUMMARY OF THE INVENTION

The main object of the present invention is to provide, a process for the preparation of enantiomerically pure (R)-l-(l-naphthyl)ethylamine of formula (Ila) by treating 1- acetylnaphthalene of formula (I) with R-selective transaminase enzyme in presence of amino donor.

The (R)-l-(l-naphthyl)ethylamine of formula (Ila) thus obtained was further converted to cinacalcet hydrochloride of formula (III).

Another object of the present invention is to provide, a process for the preparation of enantiomerically pure (S)-l-(l-naphthyl)ethylamine of formula (lib) by treating 1- acetylnaphthalene of formula (I) with S-selective transaminase enzyme in presence of amino donor.

Yet another object of the present invention is to provide, pharmaceutical compositions comprising cinacalcet hydrochloride of formula (III) obtained from intermediate (R)-l-(l- naphthyl)ethylamine of formula (Ila), prepared by the process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation of enantiomerically pure (R)- l-(l-naphthyl)ethylamine of formula (Ila) from 1 -acetylnaphthalene of formula (I) by treating it with R-selective transaminase enzyme in presence of amino donor as shown in scheme 4.

The present invention also provides a process for the preparation of enantiomerically pure (S)-l-(l-naphthyl)ethylamine of formula (lib) from 1 -acetylnaphthalene of formula (I) by treating it with S-selective transaminase enzyme in presence of amino donor as shown in scheme 4.

(Ila) (I) (Tib)

(R)-1 -( 1 -Naphthyl)ethy lamine 1 -acet lnaphthalene (S)- 1 -( 1 -Naphthyl)ethy lamine

Scheme 4

The term "enantiomerically pure" refers to >97%, >98%, >99% and 100% enantiomeric excess (ee) of one of the enantiomers of l-(l-Naphthyl) ethylamine, as determined by

HPLC.

The term "Transaminase" also referred as "Amine Transaminase (ATA)" is used to refer to a polypeptide having an enzymatic capability of transferring an amino group (NI¾) to a carbonyl group (C=0) of an acceptor molecule.

The term "Amino donor" is used to refer to any amino acid or amine that will react with a transaminase and a ketone, to produce desired amine product and a ketone by product.

The transamination reaction is carried out in presence of "Pyridoxal-phosphate (PLP)" that acts as a coenzyme. In transamination reactions using transaminase enzymes, the amine group of the amino donor is transferred to the coenzyme to produce a ketone as a by-product, while pyridoxal-5 '-phosphate is converted to pyridoxamine phosphate. The transfer of the amine group from pyridoxamine phosphate to the ketone substrate produces a chiral amine and regenerates the coenzyme.

R-selective transaminase enzyme include, but are not limited to ATA-P2-A07, ATA-025, ATA-013, ATA-033, Evo 1.2.131, Evo 1.2.133, Evo 1.2.134, Evo 1.2.137, ECS-ATA-07 and mixtures thereof; and S-selective transaminase enzyme include, but are not limited to ATA-113, ATA-237, ATA-251, ATA-256, ATA-260, and mixtures thereof.

Typical amino donors that can be used with the invention include chiral and achiral amino acids, and chiral and achiral amines. Amino donors that can be used with the invention include, by way of example and not limitation, isopropylamine, 1-phenylethanamine, and its enantiomers (S)-l-phenylethanamine and (R)-l-phenylethanamine, 2-aminobutane, 2- amino-l-butanol, l-phenyl-2-aminobutane, including both (R) and (S) single isomers where possible and including all possible salts of the amines. More preferably, the amino donor is isopropylamine thereby obtaining acetone as a by-product. Transamination of the substrates is carried out in a bioreactor using an aliquot of the enzyme with the substrate typically at a defined concentration. The reaction parameters such as pH = 6-9, temperature = 20 - 40°C, and reaction time = 12-48 hrs are maintained at levels that favor optimal biocatalytic activity and stability.

We have screened several transaminase enzymes for conversion of 1-acetylnaphtahalene of formula (I) to obtain (R)-l-(l-naphthyl)ethylamine of formula (Ila) and (S)-l-(l- naphthyl)ethylamine of formula (lib). These are summarised in Table 1.

Screening protocol: 10 mg Transaminase enzyme was dissolved in 0.9 mL buffer solution (1 M isopropyl amine, 0.1 M triethanolamine and 1 mM PLP) at 30°C. The reaction is initiated by adding O. lmL substrate-DMSO Sol (5 mg 1-acetylnaphthalene in 0.1 mL DMSO). Reaction mixture having a pH from approximately 6-9 is maintained at 25-35°C for 12-48 hrs and samples were analyzed by HPLC.

Table 1: Performance of Transaminase enzymes after screening.

Sr. Transaminase Desired Undesired

(%)-Con version

No. Enzyme Code (R)-Amine (S)-Amine

1. ATA-P2-A07 64.75 100 % 0

2. ATA-025 54.99 100 % 0

3. ATA-013 64.81 100 % 0

4. ATA-033 78.81 100 % 0

5. ATA- 113 58.44 0 100 %

6. ATA-237 62.30 0 100 %

7. ATA-251 78.72 0 100 %

8. ATA-256 52.07 0 100 %

9. ATA-260 53.48 0 100 %

10. Evo 1.2.131 9.10 98.85% 1.15% 11. Evo 1.2.133 19.13 99.2% 00.8%

12. Evo 1.2.134 7.36 98.53% 1.47%

13. Evo 1.2.137 3.99 97.33% 2.67%

14. ECS-ATA-07 17.49 99.52% 0.48%

In another aspect, the present invention also provides process for the preparation of Cinacalcet hydrochloride of formula (III) comprising:

i) reacting 1-acetylnaphthalene of formula (I) with R-selective transaminase enzyme in presence of amino donor to obtain (R)-l-(l-naphthyl)ethylamine of formula (Ila) and

ii) converting the (R)-l-(l-naphthyl)ethylamine of formula (Ila) to cinacalcet hydrochloride of formula (III).

Intermediate (R)-l-(l-naphthyl)ethylamine of formula (Ila) made by the process of the present invention can be converted to cinacalcet hydrochloride of formula (III) by the methods known in the literature.

In another aspect, the present invention also provides pharmaceutical compositions comprising cinacalcet hydrochloride of formula (III) obtained from intermediate (R)-l-(l- naphthyl)ethylamine of formula (Ila), prepared by the process of the present invention. The pharmaceutical composition may be formulated in conventional manner using one or more physiologically acceptable carriers, excipients, or diluents.

To understand the present invention following preparative and testing examples are set forth, which are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

EXAMPLES: Source of enzyme:

1. Supplier: Codexis; Kit Name: Codex^® ATA Screening Kit; Supplier

ATASK-200250P; Kit content: 24 transaminases and co- factor PLP. 2. Supplier: Evocatal GmbH; Kit Name: ATA Screening Kit; Supplier code: ECS- ATA-kit; Kit content: 7- transaminases enzyme.

3. Supplier: Enzymicals AG; Kit Name: Transaminase Kit; Supplier code: EVO- 1.2.800; Kit content: 19 transaminases enzyme. Buffer solution preparation: To a 10 mL of DM water added 1.25 mL isopropylamine, 0.25 gm of triethanolamine and 4mg PLP. Dissolved to get clear solution and made up 15 mL with water with pH ~ 7.5.

The enantiomeric purity was determined by HPLC method using the following parameters: Column: Chiralpak IB (4.6x250 mm) 5 μ; Flow rate: 1.0 ml/min (isocratic); Wavelength: UV at 223 nm; Injection volume: 5 μΐ; Column oven temperature: 25° C; Auto sampler temperature: 10° C; Run time: 25 min and Mobile phase: n-heptane: ethanol: trifluoroacetic acid: diethyl amine (90: 10:0.02:0.02).

Example 1: Preparation of (R)-l-(l-naphthyl)ethylamine (Ila).

10 mg Transaminase enzyme ATA-P2-A07 was dissolved in 0.9 mL buffer solution (1 M isopropyl amine, 0.1 M triethanolamine and 1 mM PLP) at 30°C. The reaction is initiated by adding O.lmL substrate-DMSO Sol (5 mg 1-acetylnaphthalene in 0.1 mL DMSO). Reaction mixture was maintained at 30 C for 24 hrs and samples were analyzed by HPLC. 64.75% conversion was obtained with 100% R-isomer. Example 2: Preparation of (S)-l-naphthylethylamine (lib).

10 mg Transaminase enzyme ATA-113 was dissolved in 0.9 mL buffer solution (1 M isopropyl amine, 0.1 M triethanolamine and 1 mM PLP) at 30°C. The reaction is initiated by adding O.lmL substrate-DMSO Sol (5 mg 1-acetylnaphthalene in 0.1 mL DMSO). Reaction mixture was maintained at 30 C for 24 hrs and samples were analyzed by HPLC. 58.44% conversion was obtained with 100% S-isomer.

Example 3: Preparation of cinacalcet hydrochloride (III):

Reaction mixture from example 1 was treated with 4.20 mg of l-(3-chloroprop-l-en-l- yl)-3-(trifluoromethyl)benzene in presence of K2CO₃ in water, heated the mixture to 70- 100°C for 2 hours and then extracted with dichlorome thane. The residue obtained by removing the dichloromethane is reduced with Pd/C in methanol to give reaction mixture containing cinacalcet hydrochloride (III).

Example 4: Preparation of cinacalcet hydrochloride (III):

Reaction mixture from example 1 was treated with 4.23 mg of l-(3-chloropropyl)-3- (trifluoromethyl)benzene in presence of K2CO₃ in water, heated the mixture to 70-100°C for 2-4 hours and then extracted with dichloromethane. Dichloromethane is distilled out to give reaction mixture containing cinacalcet hydrochloride (III).

Claims

1. A process for preparation of enantiomerically pure (R)-1-(1-Naphthyl)ethyl of formula (Ila) comprising:

(I) (Ila)

1 -acety lnaphthalene (R)- 1 -(1 -Naphthyl)ethylamine treating 1-acetylnaphthalene of formula (I) with R-selective transaminase enzyme in presence of amino donor.

2. A process for preparation of cinacalcet hydrochloride of formula (III) comprising:

(III) i) reacting 1-acetylnaphthalene of formula (I) with R-selective transaminase enzyme in presence of amino donor to obtain (R)-l-(l- Naphthyl)ethylamine of formula (Ila) and

ii) converting the (R)-1-(1-Naphthyl)ethylamine of formula (Ila) to Cinacalcet hydrochloride of formula (III).

3. The process according to claim 1 or 2, wherein the R-selective transaminase enzyme is selected from ATA-P2-A07, ATA-025, ATA-013, ATA-033, Evo 1.2.131, Evo 1.2.133, Evo 1.2.134, Evo 1.2.137, ECS-ATA-07 and mixture thereof. A process for preparation of enantiomerically pure (S)-1-(1-Naphthyl)ethyl of formula (lib) comprising:

(I) (li )

1 -acetylnaphthalene (S)-1-(1-Naphthyl)ethylamine treating 1 -acetylnaphthalene of formula (I) with S-selective transaminase enzyme in presence of amino donor.

The process according to claim 4, wherein the S-selective transaminase enzyme is selected from ATA-237, ATA-251 , ATA-256, ATA-260 and mixture thereof.

The process according to claim 1, 2 or 3, wherein the amino donor is selected from isopropylamine, 1-phenylethanamine, (S)-l-phenylethanamine, ( )-l- phenylethanamine, 2-aminobutane, 2-amino-l-butanol, l-phenyl-2-aminobutane.

The process according to claim 6, wherein the amino donor is isopropylamine.

The process according to claim 1 or 4, wherein pH is in the range 6-9.

The process according to claim 1 or 4, wherein the process is carried out at a temperature of 20-40 °C.

A pharmaceutical composition comprising cinacalcet hydrochloride of formula (III) obtained according to claim 2 and pharmaceutically acceptable carrier, excipient, or diluent.