Deriving Atom Economy Approach by Employing Dynamic Resolution of (3-Methoxy Phenyl)-(3-N, N-Dimethyl Amino)-2-Methyl Propanone

 

G. Venkanna^1,2, G. Madhusudhan¹*, K. Mukkanti², K. Chandra Babu¹,  P. Venkateswarlu¹

¹Department of Research and Development, Inogent Laboratories Private Limited (A GVK BIO Company),

28A, IDA, Nacharam, Hyderabad 500 076, India

²Centre for Chemical Sciences and Technology, Institute of Science and Technology,

Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500 072, India

*Corresponding Author E-mail: madhusudhan.gutta@yahoo.com

Racemic 3-Subsituted phenyl-3-(dimethylamino)-2-methylpropan-1-one resolved by means of a dynamic diastereomeric salt formation using di-Benzyl-L-tartaric acid with PTSA. The salts are formed in excellent yields and diastereomeric excesses.

 

 

 

INTRODUCTION  

Tapentadol Hydrochloride [1] was approved by the FDA in November 2008 for the treatment of moderate to severe acute pain. It is a centrally acting analgesic that acts as both an agonist at the l-opiod receptor and as a norepinephrine re-uptake inhibitor, allowing it to have efficacy similar to potent narcotic analgesics but without their side effects.80 The drug was developed by Grunenthal and Johnson and Johnson and was marketed starting in 2009.It is a novel opioid receptor (MOR) agonist. Its relative efficacy compared with morphine is 88% [2].

 

Fig. 1

 

As part of our efforts to develop an industrially scalable synthesis of Tapentadol hydrochloride, we have examined other methods for the preparation of enantiomerically enriched 3-(dimethylamino)-1-(3-subsituted phenyl)-2-methylpropan-1-one.The dynamic entrainment of 3-(dimethylamino)-1-(3-subsituted phenyl)-2-methylpropan-1-one is a kinetic process and so requires tightly controlled conditions to be effective. We therefore wished to devise an alternative method for the resolution and believed that a process under thermodynamic control would be more reliable [3-4] and the improved route disclosed in recent patents is described [5-6].

 

MATERIAL AND METHODS:

All reagents and solvents employed were of commercial grade and were used as such, unless otherwise specified. Reaction flasks were oven-dried at 200°C, flame-dried and flushed with dry nitrogen prior to use. All moisture and air-sensitive reactions were carried out under an atmosphere of dry nitrogen. TLC was performed on Kieselgel 60 F₂₅₄ silica-coated aluminium plates (Merck) and visualized by using either UV light (λ = 254 nm) or by spraying with a solution of ninhydrin or KMnO₄. Organic extracts were dried over anhydrous Na₂SO₄. Flash column chromatography was performed using Kieselgel 60 brand silica gel (230-400 mesh). The melting points were determined in an open capillary tube using a Büchi B-540 melting point instrument and were uncorrected. Optical rotations were measured on an Autopol V, serial number 80455 (manufactured by Rudolph Research Analytical, Hackettstown, NJ, USA) at the sodium D line (589 nm) and are reported as follows: [α]^t°C_D (concentration in g/100 mL, solvent). The IR spectra were obtained on a Nicolet 380 FT-IR instrument (neat for liquids and as KBr pellets for solids). NMR spectra were recorded with a Varian 300 MHz Mercury Plus Spectrometer at 300 MHz (¹H) and at 75 MHz (¹³C). Chemical shifts were given in ppm relative to trimethylsilane (TMS). Data are reported as follows: s, singlet; d, doublet; t, triplet; q, quartet; qn, quintuplet; m, multiplet; and br, broad. Mass spectra were recorded on Waters quattro premier XE triple quadrupole spectrometer using either electron spray ionisation (ESI) or atmospheric pressure chemical ionization (APCI) technique.

 

Prepartaion of 3-(dimethylamino)-l-(3-methoxy phenyl)-2-methyl-l- propanone, 3 from 2:

To a stirred solution of l-(3-methoxyphenyl)- l-propanone (2) (25 g, 0.15 mole) in 2-propanol (50 mL), Dimethylamine hydrochloride (24.8 0.3mole g), paraformaldehyde (11.4g 0.38mole g) and aqueous HCl solution (3.6 ml, 35percent w/w) was added  at <25°C. After the mixture was agitated for 5h at 83°C and then sampled for TLC. Upon completion of (2), solvent (2-propanol) was removed by distillation under reduced pressure at <40°C.  The obtained residue is partitioned between water (75 mL) and toluene (25 mL). The toluene layer was separated and discarded, the aqueous layer was cooled to 0-5^o C and pH was adjusted to 10-11 with aqueous sodium hydroxide. The separated organic layer and the aqueous phase were twice extracted with toluene (50 mL). The combined organic layer was washed with water (75 mL), dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure gave the brown colored oily liquid (32.5 g, Yield: 97%).

 

¹H NMR spectrum (CDCl₃/TMS): (ppm) δ 1.2 (s, 3H  –CH-CH₃), 2.2 [s, 6H  -N(CH₃)₂],  2.3 [m, 1H  -CH₂ -(CH₃)₂], 2.8  [m, 1H  -CH₂ -(CH₃)₂], 3.7 (m, 1H  -CH-CH₃), 3.9 (s, 3H  –ArO -CH₃),  7.16  (d, 1H  Ar-CH), 7.4-7.6 (m, 3H  Ar-CH); MS (ES): m/z 222[ M+1] ⁺.

 

(S)-3-(dimethylamino)-1-(3-methoxy phenyl)-2- methylpropan-1-one (2R,3R)-O,O'-dibenzoyltartrate, 4 from 3:

(2R,3R)-O,O'-Dibenzoyl tartaric acid monohydrate (L-DBTA) (42.6g, 0.113 mol) was dissolved in a mixture of methanol (11.3 mL), acetone (50 mL) and 3-  (dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (25gm 0.113 mole), 4-methylbenzenesulfonic acid (PTSA (cat)) was added at ambient temperature. The reaction mixture was heated to 40°C for 24 hours and allowed to cool to 25 ⁰C. The suspension was siphoned off and (S)-3- (dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (2R,3R)-O,O'-dibenzoyltartrate was obtained as a colorless solid [57.5g, 85%(overall), de 98%].

 

¹H NMR spectrum (CDCl₃/TMS): (ppm) δ 2.2 [s, 6H  - N(CH₃)₂], 3.9 (s, 3H  -OCH₃),  4.0 (m, 1H – CH- CH₃), 5.8 (s, 2H  2(CH) DBTA), 7.2 (m, 1H  Ar-CH), 7.2 (d, 1H Ar-CH), 7.44-7.7 (m, 9H Ar-CH), 8.0 (d, 4H –Ar-CH) ; MS (ES): m/z 557[ M+1] ⁺.

 

(2S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2- methylpropan-1-one, 5 from 4:

Compound (4) (50.0 g, 0.08 mole) is suspended in water (100 mL), toluene (150 mL) and pH was adjusted to 9-10 with 10% aqueous sodium hydroxide. The phases were separated and the aqueous phase was twice extracted with toluene (100 mL). The combined organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure, to give (5) as brown oily liquid (17 g, Yield: 91%).

 

¹H NMR spectrum (CDCl₃/TMS): (ppm) δ 1.2 (s ,3H –CH-CH₃), 2.2 [s, 6H -N(CH₃)₂], 2.3 [m, 1H -CH₂ -(CH₃)₂], 2.8 [m, 1H -CH₂ -(CH₃)₂], 3.7 (m, 1H -CH-CH₃), 3.9 (s, 3H –Ar O -CH₃), 7.16 (d, 1H Ar-CH), 7.4-7.6 (m, 3H Ar-CH); MS (ES): m/z 222 [ M+1] ⁺.

 

(2S)3-(dimethyl amino)1-3-(methoxy) phenyl)-2-methyl-pentane-3-ol (6):

 Its ¹H NMR spectrum (CDCl₃/TMS) showed signals at d (ppm):  2.2 (m, 1H –C-OH), 2.25 [s, 6H N(CH₃)₂], 2.1-2.2 [m, 2H -CH₂ -(CH₃)₂], 2.2 (s, 6H -CH₂CH₃), 3.9 (s, 3H  –ArO -CH₃),7.16 (d, 1HAr-CH), 7.4 (d, 1H Ar-CH) 7.5 (s, 1H Ar-CH) 7.6 (d 1H Ar-CH).Its Mass spectrum showed the molecular ion peak at 252 corresponding to a molecular mass of 251.

 

(R) 3-(3-(methoxy)phenyl)-N,N,2-trimethyl-pent3-en-1-amine (7):.

Its ¹H NMR spectrum (CDCl₃/TMS) showed signals at d (ppm):  (ppm): 1.1(s, 3H), 1.5(d, 3H), 2.1 [s, 6H N(CH₃)₂], 2.1-2.2 [m, 2H -CH₂ -(CH₃)₂], 2.25 (s, 3H -CH-CH₃), 2.6 (m, 1H  -CH-CH₃), 3.9 (s, 3H  O -CH₃), 5.5 (m, 1H Allyl CH), 7.16 (d, 1H Ar-CH), 7.4 (d, 1H Ar-CH) 7.5 (s, 1H Ar-CH) 7.6 (d 1H Ar-CH).

 

(2R,3R)-3-(3-(methoxy)phenyl)-N,N,2-trimethyl-pentane-1-amine (8):

Its ¹H NMR spectrum (CDCl₃/TMS) showed signals at d (ppm):  0.7(t, 3H CH₂CH₃), 1.6(d, 3H CH CH₃), 1.5-1.8 (m, 2H CH₂N(CH₃) 2-2.4 [m, 2H -CH₂ -CH₃], 2.6 -27 (m, 8H N(CH₃)₂), 3.9 (s, 3H  O -CH₃), 6.6 (d, 1H Ar-CH), 6.7 (d, 1H Ar-CH), 6.8 (d, 1H Ar-CH) 7.3 (t, 1H Ar-CH) 12.0 (br s, 1H HCl). Its Mass spectrum showed the molecular ion peak at 236 corresponding to a molecular mass of 235.

 

(1R,2R)-3-3-(dimethyl amino 1- ethyl)2-(methoxy)propyl)-phenol hydrochloride (1):

Its ¹H NMR spectrum (CDCl₃/TMS) showed signals at d (ppm):  0.7(t, 3H CH₂CH₃), 1.6 (d, 3H CH CH₃), 1.5-1.8 (m, 2H CH₂N(CH₃) 2-2.4 [m, 2H -CH₂ -CH₃], 2.6 -27 (m, 8H  N(CH₃)₂), 6.6-7.3 (t, 1H Ar-CH), 7.3 (t, 1H Ar-CH) 12.0 (br s, 1H HCl).Its Mass spectrum showed the molecular ion peak at 222 corresponding to a molecular mass of 221.Based on the spectral data the compound has been characterized as(1R, 2R)-3-(3-dimethylamino-1-ethyl-propyl)-phenol hydrochloride) (1).

 

2,5-dihydroxyfuran-3,4-diyl dibenzoate (Impurity-9):

Its ¹H NMR spectrum(9) (CDCl₃/TMS)  showed signals at d (ppm): 47 (t, 2H),7.60 (m, 1H),8.13 (d, 2H), 12.90 (s, 1H); Its ¹³C NMR spectrum(CDCl₃/TMS)  showed signals at d (ppm): 167.4, 132.8, 130.9,129.3,128.5.Its Mass spectrum  showed the molecular ion peak at 341 corresponding to a molecular mass of 340. Based on the spectral data the compound has been characterized as 2,5-dihydroxyfuran-3,4-diyl dibenzoate (Impurity-9).

 

1-(3-methoxyphenyl)-2-methylprop-2-en-1-one (Impurity-10):

Its ¹H NMR spectrum(10) (CDCl₃/TMS)  showed d (ppm): 7.37 (d, 1H), 7.34 (m, 2H),7.05 (d, 1H), 5.98 (s, 1H), 5.60 (s, 1H), 3.85 (s, 3H), 2.05 (s, 3H). Its Mass spectrum showed the molecular ion peak at 177.05 corresponding to a molecular mass of 176. Based on the spectral data the compound has been characterized as1-(3-methoxyphenyl)-2-methylprop-2-en-1-one (Impurity-10).

 

3-isopropoxy-1-(3-methoxyphenyl)-2-methylpropan-1-one (Impurity-11):

Its ¹H NMR spectrum (11) (CDCl₃/TMS) showed d (ppm):  7.23-7.45 (m, 3H), 7.05 (d, 1H), 3.83 (s, 3H), 3.39-3.64 (m, 3H), 3.38 (m, 1H), 1.20 (s, 6H). Its Mass spectrum showed the molecular ion peak at 237 corresponding to a molecular mass of 236. Based on the spectral data the compound has been characterized as3-isopropoxy-1-(3-methoxyphenyl)-2-methylpropan-1-one (Impurity-11).

 

RESULTS AND DISCUSSION:

We conducted a screen of chiral acids against 3-(dimethylamino)-1-(3-subsituted phenyl)-2-methylpropan-1-one and found that di-benzoyl-L-tartaric acid was an effective resolving agent. With 1.0 equivalent of di-benzoyl-L-tartaric acid with PTSA, (dimethylamino)-1-(3-subsituted phenyl)-2-methylpropan-1-one 1:1 salt was isolated in 85% yield. 

Scheme-1

Table. 1: Study of Dynamic resolution by various solvents in L-DBTA:

 

Table. 2: Dynamic resolution was studied by changing L-DBTA mole ratios:

 

This salt contained 3-(dimethylamino)-1-(3-subsituted phenyl)-2-methylpropan-1-one of 99% e.e. assuming a 'normal' classical resolution, the theoretical maximum yield of this I: 1 salt was only 50 %. The initial experimental yield of 85% clearly indicated that 3-(dimethylamino)-1-(3-subsituted phenyl)-2-methylpropan-1-one was racemising under the 'acidic' reaction conditions, allowing material to be funnelled through into one diastereomeric salt in a dynamic diastereomeric salt resolution.

 

Table.3: Acid catalyzed induced L-DBTA:

 

Table. 4: Dynamic resolution was studied by changing various chiral acids:

 

The dynamic nature of these resolutions permits yields in excess of those which would be obtained from a non-dynamic classical resolution. Moreover, their thermodynamic nature renders them reliable and scaleahle particularly in comparison to our experiences with the entrainment of Tapentadol. Ketone was treated with paraformaldehyde and DMA HCl (Mannich reaction) at reflux temperature and the resulting amine was collected in 90% yield.

 

 

The amine compound (3) amine was crystallized with L-(-)-dibenzoyl tartaric acid monohydrate with PTSA in Mehanol/acetone to give the desired enantiomer as salt in 85% yield. The free base of was generated by reaction with aqueous sodium hydroxide in 95% yield and then treated with ethylmagnesium bromide in THF followed by stirring at room temperature to give tertiary alcohol in 89% yield. Alcohol was treated with HCl to give the corresponding alkene which was then treated with 10% Pd/C and hydrogenated at 5 bar at ambient temperature. These hydrogenolytic conditions effected reductive cleavage with the retention of stereochemistry. Demethylation with Aq. HBr and IPA. HCl to allowing the product to crystallize out gave the desired terpentadol hydrochloride in 89% yield with 99% purity and 99.0% ee.

Synthesized optically active 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one by asymmetric transformation in acetone and methanol medium using (+) or (‒) tartaric acid salt and further hydrolysis of salt in sodium hydroxide 10% in water and toluene gave only ~80% optically active amine. This prompted us to develop an efficient crystallization induced dynamic resolution for 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one derivative. dynamic resolution (CIDR) is an attractive approach in which one of diastereomers crystallizes preferentially with high selectivity. Among 3-(dimethylamino)-1-(3-subtituted-phenyl)-2-methylpropan-1-one derivatives, we focused on 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one and herein wish to report the dynamic resolution (CIDR) of racemic 3-Subsituted phenyl-3-(dimethylamino)-2-methylpropan-1-one.

 

First, racemic 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one was synthesized by literature method. We investigate the dynamic resolution to obtain optically active 3-(dimethylamino)-1-(3-methoxyphenyl) -2-methylpropan-1-one through the formation of optically active salt with L-DBTA, as a resolving agent as shown in Scheme-2.

 

 

Scheme -2: Crystallization induced dynamic resolution of 3-(dimethylamino)-1-(3-methoxy phenyl)-2-methylpropan-1-one with L-DBTA and PTSA.

 

 

A solution of racemic 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one in acetone/ methanol was mixed with a solution of L-dibenzoyl tartaric acid and PTSA 35-40 temperature. As the crystals begin to separate, the mixture was repeatedly subjected to heating (<40^oC) and cooling (~20^oC) for 24 hr. The precipitated crystals were filtered, washed with acetone and dried furnished optically pure 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one․ L-DBTA as 70% yield. The remaining filtrate was heated and cooled for one more time to yield 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one․ L-DBTA as 15% yield (total 85% yield, 99% de).

 

Table- 5: Temperature studies on L-DBTA:

 

In order to obtain free form of (S)- 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one,basification condition was optimized with weak bases as shown in Table 6. It was found that by stirring with 10% NaOH in ice bath results excellent yield and 98% ee.

 

Table-6. Basification of (S) - 3-(dimethylamino)-1-(3-methoxy phenyl)-2-methylpropan-1-one․ L-DBTA salt (99% de)

 

The dynamic resolution of 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one examined by electron with droning group, electron releasing group, without group.

 

Table-7.Dynamic resolution studies on 3 subsituted-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one with L-DBTA.

 

The reason for dynamic resolution the DBTA is a dicarboxylic acid and the one acid form salt with the amine group and one more acid in DBTA form hydrogen bonding with the keto group due to various substitutions on benzene the hydrogen bonging varying the dynamic resolution. The electron releasing group stabilizes the hydrogen bonding and observed more dynamic resolution where as other group like without any group or with droning groups decreases the hydrogen bonding and makes less favors for dynamic resolution.

 

This is particularly noteworthy in that the chiral salt L-DBTA could be recovered in 80% yield after a simple acid-base work-up operation from the main reacquired enantiomer. But the reaming 20% salt with opposite isomer in the filter mother liquor. during recover the 20% salt in a pure enentomeric form mls we have observed the DBTA get lactone ring  impurity (9) form in acidic reaction mass during solvent removal. We have identified and isolated and characterized the compound (9) mentioned below.

 

 

To avoid the formation of 2,5-dihydrofuran-2,5-dihydroxyfuran-3,4-diyl dibenzoate impurity (9) and to recover the 20% of L-DBTA ina pure enantomeric form the total MLs cooled and basified with 10% NaOH solution and extracted with toluene he unwanted isomer removed and the L-DBTA remains in aqueous solution by simple acidification 20% of L-DBTA recovered as a pure enatiomeric form.

 

During the preparation of compound (2), we observed impurity-(10) and impurity-(11), these impurities eliminated during the toluene washing.

 

The Grignard reaction of(2S)3-(dimethyl amino)1-3-(methoxy)phenyl)-2-methyl-1-propanone (5) with ethyl magnesium chloride to form (2S)3-(dimethyl amino)1-3-(methoxy)phenyl)-2-methyl-pentane-3-ol (6).

 

The dehydration reaction of  (2S)3-(dimethyl amino)1-3-(methoxy)phenyl)-2-methyl-pentane-3-ol (6) with acid to form (R) 3-(3-(methoxy)phenyl)-N,N,2-trimethyl-pent3-en-1-amine (7). Compound (7) with Pd/C to form (2R,3R)-3-(3-(methoxy)phenyl)-N,N,2-trimethyl-pentane-1-amine hydrochloride salt (8). Demethylation of (2R,3R)-3-(3-(methoxy)phenyl)-N,N,2-trimethyl-pentane-1-amine (8) with hydro bromic acid  followed by hydro chloride salt to form final (1R,2R)-3-3-(dimethyl amino 1- ethyl)2-(methoxy)propyl)-phenol hydrochloride (1).

 

CONCLUSIONS:  

In summary, we describe herein the synthesis of Tapentadol hydrochloride with atom economy process by systematic study of dynamic resolution of (3-Methoxy phenyl)-(3-N,N-dimethyl amino)-2-methyl propanone. This process study use full for large scale synthesis of tapentadol hydrochloride with maximum yield and quality without losing other isomer.

 

ACKNOWLEDGEMENTS:

Financial support from the Inogent Laboratories Private Limited (A GVK BIO Company) is gratefully acknowledged.

 

REFERENCES  

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Received on 04.02.2015         Modified on 05.03.2015

Accepted on 19.03.2015         © AJRC All right reserved