Indian Patents. 251844:METHOD FOR PRODUCING 1-FORMAMIDO-3,5-DIMETHYLADAMANTANE

Title of Invention	METHOD FOR PRODUCING 1-FORMAMIDO-3,5-DIMETHYLADAMANTANE
Abstract	The invention relates to a method for producing 1-formamido-3,5-dimethyladamantane in only two reaction steps by direct formamide formation of 1,3-dimethyladamantane, the 1,3-dimethyladamantane being reacted with formamide in concentrated acids.

Full Text	FORM 2 THE PATENTS ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. ' METHOD FOR PRODUCING l-FORMAMIDO-3,5-DIMETHYLADAMANTANE ' 2. 1. (A) MERZ PHARMA GMBH & CO. KGAA (B) A Company incorporated under the Laws of Germany (C) Eckenheimer Landstrasse 100, 60318 Frankfurt/Main Germany The following specification particularly describes the invention and the manner in which it is to be performed. 28 JUL 2008 Subject-matter or the invention is a method for preparing 1-formamido-3,5-di- methyladamantane, which is an important intermediate for the manufacture of 1-amino-3,5-dimethyladamantane that is used for the treatment of Alzheimer's disease and that is known under the agent name memantine. It is sold in Europe (and in numerous non-European countries) under the trademarks axura and ebixa® and under namenda® in the USA. The manufacture of 1-formamido-3,5-dimethyladamantane starting from l-bromo-3,5-dimethyiadamantane and formamide is already known as such. 1-amino-3;5-dimethyladamantane as substancs is already known from DE 2 318 461 Al Its use for prevention and treatment of cerebral ischemia is described in EP 0 392059 B1. Accordingly, the synthesis of 1-formamido-3,5-dimethyladamantane, which is used for the manufacture thereof, takes place until now by a halogenation of 1,3-dimet'nyiadamantane and subsequent forrmamidation. Afterwards, 1-formamido-3,5-dirnethyladamantane is hydrolyzed to the amine by means of diluted hydrochloric acid. However, starting from 1,3-dimethyiadamantane, this synthesis method requires three synthesis steps in order to arrive at memantine: halogenation, formamidaticn, and acidic hydrolysis. Thereby; the use of poisonous, elemental chlorine or bromine in excess Is required; this causes additional costs for waste disposal and may lead to undesired by-products. Thus, the problem of the invention was to provide a method for the formamidation of 1,3-dimethyiadam-antane, which is simpler and which can be carried out with iess poisonous or expensive reagents. In the international patent application WO 2006/010362 A1, a method for preparing derivatives of 3,5-substituted 1-aminoadamantane has already been described in which a 1,3-disubstituted adamantane derivative is suspended in HNO3 and H2SO4, and which is reacted with a nitrite after the addition of oleum, in contrast, in the method according to the invention, the preparation of 1-formamido-3,5-dimethy!adamantane takes place only in two reaction steps by direct formamidation of 1,3-dimethy!adamantane with formamide in concentrated acids. Preferred are 30 - 70 %, in particular 65 % nitric acid and 90-100 %, however in particular 95 - 93 % sulfuric acid. However, also 55 - 100 % phosphorus acid, perchloric acid, disulfuric acid or chlorosulfuric acid can be employed. In general, the reaction takes p;ace at -40 °C up to 50 °C, however preferably at 0 °C. In the method according to the invention, mostly yields of 40 - 95 % are achieved. Said method is not only characterized by being free of halides, however has also a more favourable impurity profile, because it runs in high yields and only with a small amount of by-products, and thereby even tolerates impurities in the starting materials. According to GO-MS, in the formamidation only non-reacted educt as well as 3,5-dimethyladamantane-1-ol could be detected as by-products. Even a preparation of the starting material in situ from cheap precursors is possible so that the desired end product is obtainable in a "one pot" method. Thereby, 1,3-di-methyladamantane to be reacted with formamide is obtained in situ from a hydrocarbon having the empirical formula C12H20 by cationic rearrangement under comparable reaction conditions, which are also applied for the formamidation. For example, one obtains the precursors by means of perhydrogenation of acenaphthene, acenaphthaiene or methylcyciopentadiene dimer. Subsequent, the formamidation of the produced dimethyladamantane is-carried out under acid conditions in the same reaction vessel. The treatment of perhydrogenated methycyclopentadiene dimer with concentrated acids allows the manufacture of the starting materia! 1,3-dimethyladamantane in situ prior to the formamidation according to the following reaction: 3 hydrogenation rearrangement The method described in the international application PCT/DE2005/001304 is based on the generation of carbocations in concentrated acids, which can be scavenged by a nucleophile such as a nitrile, and which are converted to the ' corresponding 1-amidoadamantane derivatives in aqueous processing according to the following reaction: On contrast, the method according to the invention for preparing 1-formamido-3,5-dimethyladamantane allows milder reaction conditions and the complete avoidance of the application of oleum or 100 % nitric acid. Furthermore, formamide is used as nucleophile, whereby as reaction product 1-formamido-3,5-dimethyladamantane is produced that can be hydrolyzed under considerably milder conditions compared to other amides. So, for example, 1-acetamido-3,5-dimethyladamantane is cleaved by heating NaOH for several hours in aqueous or alcoholic base or in concentrated hydrochloric acid (36 - 37 %) to the free 1-amino-3,5-dimethyladamantsne. whereas the cleavage of the formamide already succeeds with diluted hydrochloric acid within two hours at 100 oC. The invention is specified by the following examples: Example-1 - Synthesis of 1-formamido-3,5-dimethyladamantane in sequence, 4 ml 65 % technical nitric acid and then within three hours 50 ml 93 % technical sulfuric acid are added to 6.572 g (40 mmol) 1,3-dimethyladamantane at 0 °C It is stirred over night at 0 °C and the mixture is poured at 0 oC onto 100 ml formamide in 4 a round bottom flask which is provided with a drying tube. This mixture is stirred for 30 min at 0 oC and for 90 min at room temperature and 200 mL dichioromethane and 200 mL water are added. After phase separation, the organic phase is washed with water and 2 % NaHCO3-soiution, is dried over Na2SO4 and is freed from solvents at the rotary evaporator. The remaining oil is chromatographically purified (SiO2, CHCl3/acetone (20:1), R, = 0.39). 7.41 g (89.3 %) of the formamide are obtained as a nearly colourless solid. 1H-NMR (CDCI3, TMS, 400.13 MHz) : 6 = 0.87 ppm, s, 6 H; 1,15 ppm, s, 2 H: 1.2- 1.35 ppm, m, 4H; 1.35-1.55 ppm, m, 4H; 1.65 -1.78 ppm, m, 2 H; 2.10 - 2.27 ppm, m, 1 H; 5.90 and 7.21 ppm; each br., s, 1 H; 5.02, 8.20 and 8.27 ppm. each s., 1 H. 13C-NMR (CDCI3, TMS, 100.61 MHz) : δ-29,45, 30.01, 32.00, 40.21, 41.85, 47-53, 49.94, 51.83, 160/15/162.24 ppm. MS: m/z = 207 (M*), 192, 150, 136, 106, 91, 79. Example 2 - Hydrolysis of l-Forrnyi-3,5-dimethyiadamantane to 1-Amino-3,5-di- methyladamantane hydrochloride (Memantine) 0.02 mmol 1-formyl-3,5-dimethyladamantane (4.14g) are refluxed for 24 hours in 100 mL 15 % hydrochloric acid. After cooling, the precipitate is filtered off, is dissolved in methanol and is precipitated by addition of ethyl acetate (yield 80 %). 5 We claim : 1. Method for preparing 1-formamido-3,5-dimethyladamantane by direct formamidation of 1,3-dimethyladamantane, characterized in that said 1,3-dimethyladarnantane is reacted with formamide in concentrated acids under the proviso that neither SO3-containing sulfuric acid nor 100 % nitric acid is used. 2. Method according to claim 1, characterized in that said 1,3-dimethyladamantane is prepared from a hydrocarbon precursor having the emoirica! formula C12H2o by cationic rearrangement in a separated reaction or in situ prior to the direct formamidation. 3. Method according to claims 1 and 2, characterized in that nitric acid and sulfuric acid are employed as concentrated acids. 4. Method according to claim 3, characterized in that said nitric acid is 30 - 70 % and said sulfuric acid is 90 - 100 %, if HNO3 and M2SO4 are used, 5. Method according to claims 1 and 2, characterized in that said 1-formamido-3,5-dimethyladamantane is converted to 1-amino-3,5-dimethyladamantane by hydrolysis. 6. Method according to claim 5, characterized in that the hydrolysis takes place with aqueous hydrochloric acid. 6 7. ' METHOD FOR PRODUCING l-FORMAMIDO-3,5- DIMETHYLADAMANTANE 'as claimed substantially as herein described with forgoing description & drawings. Dated this 25th day of July 2008. For and on Behalf of Applicant

Full Text

FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. ' METHOD FOR PRODUCING l-FORMAMIDO-3,5-DIMETHYLADAMANTANE '
2.
1. (A) MERZ PHARMA GMBH & CO. KGAA
(B) A Company incorporated under the Laws of Germany
(C) Eckenheimer Landstrasse 100, 60318 Frankfurt/Main Germany

The following specification particularly describes the invention and the manner in which it is to be performed.

28 JUL 2008

Subject-matter or the invention is a method for preparing 1-formamido-3,5-di-
methyladamantane, which is an important intermediate for the manufacture of 1-amino-3,5-dimethyladamantane that is used for the treatment of Alzheimer's disease and that is known under the agent name memantine. It is sold in Europe (and in numerous non-European countries) under the trademarks axura and ebixa® and under namenda® in the USA.
The manufacture of 1-formamido-3,5-dimethyladamantane starting from l-bromo-3,5-dimethyiadamantane and formamide is already known as such.
1-amino-3;5-dimethyladamantane as substancs is already known from DE 2 318 461 Al Its use for prevention and treatment of cerebral ischemia is described in EP 0 392059 B1. Accordingly, the synthesis of 1-formamido-3,5-dimethyladamantane, which is used for the manufacture thereof, takes place until now by a halogenation of 1,3-dimet'nyiadamantane and subsequent forrmamidation. Afterwards, 1-formamido-3,5-dirnethyladamantane is hydrolyzed to the amine by means of diluted hydrochloric acid.
However, starting from 1,3-dimethyiadamantane, this synthesis method requires three synthesis steps in order to arrive at memantine: halogenation, formamidaticn, and acidic hydrolysis. Thereby; the use of poisonous, elemental chlorine or bromine in excess Is required; this causes additional costs for waste disposal and may lead to undesired by-products.
Thus, the problem of the invention was to provide a method for the formamidation of 1,3-dimethyiadam-antane, which is simpler and which can be carried out with iess poisonous or expensive reagents.

In the international patent application WO 2006/010362 A1, a method for preparing derivatives of 3,5-substituted 1-aminoadamantane has already been described in which a 1,3-disubstituted adamantane derivative is suspended in HNO3 and H2SO4, and which is reacted with a nitrite after the addition of oleum, in contrast, in the method according to the invention, the preparation of 1-formamido-3,5-dimethy!adamantane takes place only in two reaction steps by direct formamidation of 1,3-dimethy!adamantane with formamide in concentrated acids.
Preferred are 30 - 70 %, in particular 65 % nitric acid and 90-100 %, however in particular 95 - 93 % sulfuric acid. However, also 55 - 100 % phosphorus acid, perchloric acid, disulfuric acid or chlorosulfuric acid can be employed. In general, the reaction takes p;ace at -40 °C up to 50 °C, however preferably at 0 °C. In the method according to the invention, mostly yields of 40 - 95 % are achieved.
Said method is not only characterized by being free of halides, however has also a more favourable impurity profile, because it runs in high yields and only with a small amount of by-products, and thereby even tolerates impurities in the starting materials. According to GO-MS, in the formamidation only non-reacted educt as well as 3,5-dimethyladamantane-1-ol could be detected as by-products.
Even a preparation of the starting material in situ from cheap precursors is possible so that the desired end product is obtainable in a "one pot" method. Thereby, 1,3-di-methyladamantane to be reacted with formamide is obtained in situ from a hydrocarbon having the empirical formula C12H20 by cationic rearrangement under comparable reaction conditions, which are also applied for the formamidation. For example, one obtains the precursors by means of perhydrogenation of acenaphthene, acenaphthaiene or methylcyciopentadiene dimer. Subsequent, the formamidation of the produced dimethyladamantane is-carried out under acid conditions in the same reaction vessel.
The treatment of perhydrogenated methycyclopentadiene dimer with concentrated acids allows the manufacture of the starting materia! 1,3-dimethyladamantane in situ prior to the formamidation according to the following reaction:
3

hydrogenation rearrangement
The method described in the international application PCT/DE2005/001304 is based on the generation of carbocations in concentrated acids, which can be scavenged by a nucleophile such as a nitrile, and which are converted to the ' corresponding 1-amidoadamantane derivatives in aqueous processing according to the following reaction:

On contrast, the method according to the invention for preparing 1-formamido-3,5-dimethyladamantane allows milder reaction conditions and the complete avoidance of the application of oleum or 100 % nitric acid. Furthermore, formamide is used as nucleophile, whereby as reaction product 1-formamido-3,5-dimethyladamantane is produced that can be hydrolyzed under considerably milder conditions compared to other amides. So, for example, 1-acetamido-3,5-dimethyladamantane is cleaved by heating NaOH for several hours in aqueous or alcoholic base or in concentrated hydrochloric acid (36 - 37 %) to the free 1-amino-3,5-dimethyladamantsne. whereas the cleavage of the formamide already succeeds with diluted hydrochloric acid within two hours at 100 oC.
The invention is specified by the following examples:
Example-1 - Synthesis of 1-formamido-3,5-dimethyladamantane
in sequence, 4 ml 65 % technical nitric acid and then within three hours 50 ml 93 % technical sulfuric acid are added to 6.572 g (40 mmol) 1,3-dimethyladamantane at 0 °C It is stirred over night at 0 °C and the mixture is poured at 0 oC onto 100 ml formamide in
4

a round bottom flask which is provided with a drying tube. This mixture is stirred for 30 min at 0 oC and for 90 min at room temperature and 200 mL dichioromethane and 200 mL water are added. After phase separation, the organic phase is washed with water and 2 % NaHCO3-soiution, is dried over Na2SO4 and is freed from solvents at the rotary evaporator. The remaining oil is chromatographically purified (SiO2, CHCl3/acetone (20:1), R, = 0.39). 7.41 g (89.3 %) of the formamide are obtained as a nearly colourless solid.
1H-NMR (CDCI3, TMS, 400.13 MHz) : 6 = 0.87 ppm, s, 6 H; 1,15 ppm, s, 2 H: 1.2- 1.35 ppm, m, 4H; 1.35-1.55 ppm, m, 4H; 1.65 -1.78 ppm, m, 2 H; 2.10 - 2.27 ppm, m, 1 H; 5.90 and 7.21 ppm; each br., s, 1 H; 5.02, 8.20 and 8.27 ppm. each s., 1 H.
13C-NMR (CDCI3, TMS, 100.61 MHz) : δ-29,45, 30.01, 32.00, 40.21, 41.85, 47-53, 49.94, 51.83, 160/15/162.24 ppm.
MS: m/z = 207 (M*), 192, 150, 136, 106, 91, 79.
Example 2 - Hydrolysis of l-Forrnyi-3,5-dimethyiadamantane to 1-Amino-3,5-di-
methyladamantane hydrochloride (Memantine)
0.02 mmol 1-formyl-3,5-dimethyladamantane (4.14g) are refluxed for 24 hours in 100 mL 15 % hydrochloric acid. After cooling, the precipitate is filtered off, is dissolved in methanol and is precipitated by addition of ethyl acetate (yield 80 %).
5

We claim :
1. Method for preparing 1-formamido-3,5-dimethyladamantane by direct formamidation of 1,3-dimethyladamantane, characterized in that said 1,3-dimethyladarnantane is reacted with formamide in concentrated acids under the proviso that neither SO3-containing sulfuric acid nor 100 % nitric acid is used.
2. Method according to claim 1, characterized in that said 1,3-dimethyladamantane is prepared from a hydrocarbon precursor having the emoirica! formula C12H2o by cationic rearrangement in a separated reaction or in situ prior to the direct formamidation.
3. Method according to claims 1 and 2, characterized in that nitric acid and sulfuric acid are employed as concentrated acids.
4. Method according to claim 3, characterized in that said nitric acid is 30 - 70 % and said sulfuric acid is 90 - 100 %, if HNO3 and M2SO4 are used,
5. Method according to claims 1 and 2, characterized in that said 1-formamido-3,5-dimethyladamantane is converted to 1-amino-3,5-dimethyladamantane by
hydrolysis.
6. Method according to claim 5, characterized in that the hydrolysis takes place with
aqueous hydrochloric acid.
6

7. ' METHOD FOR PRODUCING l-FORMAMIDO-3,5-
DIMETHYLADAMANTANE 'as claimed substantially as herein described with forgoing description & drawings.

Dated this 25th day of July 2008.

For and on Behalf of Applicant

METHOD FOR PRODUCING 1-FORMAMIDO-3,5-DIMETHYLADAMANTANE

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