FORM - 2
THE PATENTS ACT, 1970
COMPLETE SPECIFICATION
(SECTION 10)
TITLE
A PROCESS FOR PREPARING 2, N-DIMETHYL-N-(3,3-DIPHENYL PROPYL)-1-AMINO-2-
PROPANOL
APPLICANT
SANMAR SPECIALITY CHEMICALS LTD, Having Its Registered Office At 9, Cathedral Road, Chennai 600 086, Tamil Nadu, India An Indian Company.
The following specification describes and ascertains the nature of this invention and the manner in which it is to be performed:-

Field of the invention:
The present invention relates to an improved process for the preparation of 2,N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-propanol \ starting from i-N-methylamino-3,3-diphenylpropane 2. 2,N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-propanol 2 is one of the key intermediate used in the manufacture of lercanidipine which is used in the treatment of antihypertensive.
Background of the invention:
2,N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-propanol i formula I shown in Fig-1 is a key intermediate of lercanidipine, known by its chemical name as 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-[(3,3-diphenylpropyl)methyl amino]-1,1 -dimethylethyl methyl ester disclosed in the patents EP 153016; & US 4705797. Lercanidipine is commonly used in the treatment of hypertension
A process for preparing 1-N-methylamino-3, 3-diphenylpropan-2-ene 3 was disclosed in B.P1250601 in which benzophenone is reacted with N-methyl aminoethyl triphenyl phosphonium bromide in the presence of strong base like butyl lithium. However this process involves costly, sensitive raw material namely N-methyl aminoethyl triphenyl phosphonium bromide
A process for the preparation of the N-methyl- 3,3-diphenyl propylamine 2 was disclosed in B.P.1 788915, provisional specification 6486 A.D. 1954, in which 3,3-diphenyl propan-1-ol was converted to 3- bromo-1,1-diphenyl propane using PBr3 and was treated with methyl amine to get N-methyl- 3,3-diphenyl propylamine 2. This process involves use of corrosive, moisture sensitive reagents like PBr3
Ger. Offen 1,924,687 describes a method to prepare 11-N-methyl amino-3, 3-diphenylpropan-2-ene HCI.4_ln this patent, methyl benzyl amine was added across the ethylacerylate leading to ethyl, 1-[(N-benzyl, N-methyl )amino] propanoate 5 and the resulting product was treated with phenyl magnesium bromide to give 1-N-methyl N-benzyl amino-3, 3-diphenylpropan-1-ol.HCI 6. 1-N-Methyl N-benzyl amino-3, 3-diphenylpropan-1-ol. HCI 6 was debenzylated using Pd/C and dehydrated with HCI to give 1-N-methyl amino-3, 3-diphenylpropan-2-ene HCI.4- which is shown in fig-2
2

Organic Letters, 3(17), 2781-2784; 2001 describes a novel method to produce1-N-methylamino-3, 3-diphenylpropane 2 by alkylation of 1-N-methyl amino-3-phenylpropan-3-ol. HCI 7 with benzene in the presence of trifluro methyl sulfonic acid shown in fig-3. However the method is not amenable for scale up due to the following reasons 1. Benzene is used as solvent and as reagent 2. trifluro methyl sulfonic acid is used as reagent which is very difficult to handle
A process for the preparation of 2,N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-propanol 1 was disclosed in USP 4,968,832&EP0153016 in which N-methyl- 3,3-diphenyl propylamine 2 was reacted with 1-chloro-2- methyl-2- propanol in xylene at reflux temperature . The resulting product was diluted with ether cooled to 15-20C filtered to remove starting amine hydrochloride. Further, the solvent was removed from resulting crude product and was flash chromotagraphed to get pure product in 35% yield. The method is not amenable to scale up due to column purification and is commercially less viable due to lower yield (38%)
In the absence of good process for the preparation of 2,N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-propanol i_ which is the key intermediate for lercanidipine and in the view of increasing demand for lercanidipine, need is felt a simple scalable process for the intermediate namely 2,N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-propanol 1. by every one in this field.
Object of the invention
The objective of the present invention is to provide a cost effective improved process for producing 2,N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-propanol 1 with high purity and yield by the reaction of N-methyl- 3,3-diphenyl propylamine 2 with 1-chloro-2- methyl-2- propanol in the presence of alkali metal hydroxide or of alkali metal alkoxide.
Yet another objective is process for the production of starting material namely N-methyl-3,3-diphenyl propylamine 2 by the hydrogenation of N-methyl- 3,3-diphenyl prop-3-en-1-amine 3 using metal catalyst in a organic solvent or mixture thereof
SUMMARY OF THE INVENTION
The present invention is directed to a process to produce 2,N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-propanol1_a key intermediate of lercanidipine
3

In a first embodiment the invention is directed to the process for the manufacture of 2,N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-propanol l-by reacting N-methyl- 3,3-diphenyl propylamine 2 or its salt with 1-chloro-2- methyl-2- propanol in the presence of alkali metal hydroxide or alkali metal alkoxide
In a second embodiment of the invention is to provide process for the production of the starting material namely N-methyl- 3,3-diphenyl propylamine 2 by the hydrogenation of N-methyl- 3,3-diphenyl prop-3-en-1-amine 3 using metal catalyst in organic solvent or mixture thereof.
Detailed description of the invention
According to the present invention 2,N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-
propanol 1 is prepared from N-methyl- 3,3-diphenyl prop-3-en-1-amine by a two step process as shown in the Figure-4
In the step -01 N-methyl- 3,3-diphenyl propylamine 2 was prepared by the hydrogenation of N-methyl- 3,3-diphenyl prop-3-en-1-amine 3 using metal catalyst selected from a group consist of Raney nickel, Raney cobalt, Pd/C, in oranic solvent and or a mixture of from a group consisting of polar, non polar, protic, non protic solvents, more preferably PD/C in methanol. The hydrogenation is carried out at temperature 10-50 °C for 0.5to 5hr or till the disappearance of N-methyl- 3,3-diphenyl prop-3-en-1-amine. Once the hydrogenation was complete the catalyst was filtered and the solvent was distilled out under reduced pressure.
The crude product was acidified with Cone. HCI and the HCI salt so obtained, was filtered , washed with acetone and dried.. Then the product was suspended in a organic solvent preferably heptane and was basified with sodium hydroxide. The organic layer was separated and washed with water. On distillation of organic solvent , N-methyl- 3,3-diphenyl propylamine was obtained as liquid.
N-Methyl- 3,3-diphenyl propylamine 2 or its HCI salt thus was treated with 1-chloro-2- methyl-2- propanol in the presence of alkali metal hydroxide or alkali metal alkoxide in organic solvent selected from group consist of nonplolar, polar solvents for 10-14hrs
4

The alkali metal alkoxide is selected from a group consisting alkoxide of alkanol from a group of alkanol consist of C1 to C5 alkanols with a alkali metal from a group of consist of lithium, sodium, potassium , calcium. The alkali metal hydroxide is selected from a group consisting of lithium, sodium, potassium , calcium. The preferred alkali metal alkoxide is C1, C2 alkoxide of ethanol and methanol with sodium or potassium. The most preferred alkali metal alkoxide is sodium methoxide.
Once the reaction is complete, the reaction mass was filtered. The organic solvent was removed by distillation from the filtered solution to get the crude 2,N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-propanoll. The product was then extracted using methylene chloride, the methylene chloride layer washed with brine and concentrated to give 2,N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-propanol |_with purity more then 97%.
N-methyl- 3,3-diphenyl prop-3-en-1-amine 3_used was prepared by four step process starting from benzyl methyl amine, formaldehyde and acetophenone as per procedure disclosed in J. Chem. Soc. 1510, (1950)
DESCRIPTION OF THE PREPARED EMBODIMENTS
The scope of the preferred embodiments of the present invention is further illustrated by following non-limiting examples:
EXAMPLE-01
Preparation of N-methyl- 3,3-diphenyl propylamine 2
. N-Methyl-3,3-diphenyl prop-3-en-1-amine 3 (80.0 g; 358 mole) charged to hydrogenater along with Pd/C (2 g) 10%. Chilled methanol 800 ml as charged carefully to that. The hydrogenation was carried out under 2 kg H2 pressure at 25±5°C till the completion of the reaction. Reaction completion was monitored by HPLC. After completion of the reaction, Pd/C was filtered and methanol was distillated to get residue. To the residue, acetone (160 ml) was added and chilled to 0-5°C. to that cone. HCI 55.08 ml was added slowly under stirring. The product separates out as solid which was filtered and dried to give 80gm. Yield 86% Purity 99% by HPLC, m.pt-1.75-177°C.
5


Preparation of 2,N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-propanoM
N-methyl~ 3,3-diphenyl propylamine 2 (140.0 g; 0,62 mole) and 1-chloro-2-methyl-2-propanol (100 g; .93 mole) was reacted with sodium methoxide (54 g; 0.93 mole) in methanol The reaction mixture was heated to 55-60°C with stirring till the reaction was completed (12-15 hours). After completion of reaction, the reaction mass was cool to room temperature. Solid (sodium methoxide and sodium chloride) formed in the reaction was filtered and the methanoi was removed completely by distillation. To the crude residue 200 ml of water was added slowly under stirring. The product was then extracted with methylene chloride. The methylene chloride layer washed with brine and Finally methylene chloride was distilled out under vacuum to get172 gm of 2,N-dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol - with HPLC purity 98%. Yield 98%