The present invention relates to novel improved process for synthesis of
Nordihydroguaiaretic acid (NDGA, IV)

Nordihydroguaiaretic acid (NDGA, IV) is a natural antioxidant with varied pharmacological properties, which find vast application in the pharmaceutical and cosmetic industry.

Nordihydroguaiaretic acid (NDGA) is a potent antioxidant compound found in the long-lived creosote bush. It is believed that NDGA reduces cell damage by free radicals, so under the free-radical theory of aging, could be responsible for the bush's long life.

A 1986 study involved feeding female mosquitos NDGA to test the effect on their average life span. While the usual mosquito life span was 29 days, the NDGA-fed mosquitos lived an average of 45 days—an increase of 50 percent.

A 2008 study reported that nordihydroguaiaretic acid lengthened the lifespan of male mice, but not of female mice.

The plant has been used to treat a variety of illnesses including infertility, rheumatism, arthritis, diabetes, gallbladder and kidney stones, pain and inflammation but its use is controversial. It was widely used during the 1950s as a food preservative and to preserve natural fibers but was later banned after reports of toxicity during the early 1960s. Recently, it has been used as a nutritional supplement, however renal and hepatotoxicity are reported for chronic use of creosote bush and NDGA

NDGA is a natural antioxidant that can be isolated from the resin of the leaves of Creosote bush, Larreatridentata, a desert plant indigenous to the southwestern United States and Mexico. The extraction, crystallization and use of NDGA from creosote bush as a food oxidant was approved by the Meat Inspection Division of the US war Food Administration in 1943. NDGA was widely used in the 1950s as a food preservative and also to preserve natural fibers.

(J Ethnopharmacol,2005,98,231-9).NDGA is employed as an anti-oxidant in the storage of natural and synthetic rubber. Research on NDGA and its derivatives has been attracting increasing interest in the research community since decades and continues to be so till date. Several studies suggest that NDGA could play a potent role in the cancer therapy. It was shown that NDGA could be a possible chemoprotective agent in patients at risk with lung cancer (Cancer Research, 1999, 59, 678-6184). Like other lipoxygenase inhibitors, NDGA induces a superior differentiated state and apoptosis in several human pancreatic cancer cell lines (Biochemistry and Biophysics Research Communication, 1999, 266, 392-399). Besides being a potent lipoxygenase and cyclooxygenase inhibitor (J. Pharmacology and Exptl Therapy, 1992, 261, 1143-1146), NDGA is also an inhibitor of intracellular vesicular transport (J. Cell Science, 1998, 111, 951-965).

It has been reported in the US patent 4880637 that NDGA and its analogues in combination with ionic zinc are effective in the treatment of benign, para-malignant and malignant growth of the skin without detrimental side effects associated with chemotherapy or chemosurgical techniques.

NDGA was also reported in US 4695590, as having efficacy in retarding senescence or aging in mammals. Likewise in US5008294 the effect of NDGA on human mammary carcinoma was described. US patent 6608108 relates to the use of NDGA and derivatives, in particular derivatives containing naturally occurring amino acids for the treatment of tumors and viral infections.

It has therefore been long felt need to develop process for synthesis of Nordihydroguaiaretic acid (NDGA, IV), which is chemical in nature and is pure and simple and cheaper.

These objects have been achieved by the process of the present invention which comprises a process for the preparation of Nordihydroguaiaretic acid (NDGA, IV) of Formula V of the accompanying drawings which comprises reacting Ketone of formula 1 with 1,4 Dioxane to obtain compound of formula II and said compound of formula II is further reacted in presence of palladium/carbon to obtain compound of formula III which compound of formula III is taken and reacted in aqueous HBr to obtain compound of Formula IV which if desired is subjected to fractional crystallization to obtain compound of formula V.

The reaction with 1, 4-dioxane is carried out in the presence of titanium chloride.

DETAILED DESCRIPTION OF THE INVENTION

Structurally, NDGA has two catechol groups, and a 2,3-dimethylbutane bridge. The butane bridge links two catechol moieties through a 4 position. It has a meso-form conformation of (2S, 3R), which is asymmetric structure, and is not optically active. Heller et.al, in their US patent application No. 20090306070 discussed various derivatives of NDGA and classified them as follows:

Type 1: Ether bonded NDGA, the most common NDGA derivatives, in which a substituted group is chemically bonded to one or more of the hydroxy groups of the catechol moieties.

Type 2: Ester bonded NDGA derivatives, in which a substituted group is covalently bonded to one or more of the hydroxy groups of the catechol moieties.

Type 3: End-ring NDGA derivatives, in which two hydroxy groups at the catechol moieties were linked together to form 5-6 member rings through ether or carbonate bonds.

Type 4: Di-substituted NDGA derivatives, in which one hydroxy group of the catechol is methylated, the other one is covalently bonded to a substituted group.

Type 5: Phenyl ring modifications, in which the substituted groups are chemically linked to the phenyl ring.

Type 6: Butane bridge modifications, in which two methyl groups in the bridge were removed or modified by substituted groups.

US patent 2456443 provides a synthesis for NDGA by bromination of 3,4-methylenedioxy-alkylbenzene, coupling the resultant molecules to form 2,3-bis(3,4-methylenedioxybenzyl)-butane, chlorinating this compound to form 2,3-bis(3,4-dichloromethylenedioxybenzyl)-butane, and hydrolyzing it to generate NDGA.

US patent 2644822 discloses processes for reacting benzaldehydes having a hydroxy group or a potential hydroxy (oxy) group at the 4-position (para to the aldehyde group) and at least another hydroxy or potential hydroxy group at the 3-position to produce ketone and diol intermediates, and a final nordihydroxybutanediol product. In each case, the diols are formed from ketones by means of bimolecular reduction reactions.

J. Org. Chem. 1972, 37, 4371 discloses the synthesis of NDGA by alkylation of the sodium enolate of 3,4-dimethoxypropiophenone with a-bromo-3,4-dimethoxypropiophenone to form racemic 2,3-dimethyl,1,4-bis (3,4-dimethoxyphenyl)1,4-butanedione. Cyclodehydration of the racemic diketone produces all-cis 3,4-dimethyl, 2,5-bis 3,4-dimethoxyphenyl-tetrahydrofuran, which is hydrogenated at high pressure to produce the tetramethyl ether of NDGA, followed by dealkylation to form NDGA.

US patent 3769350 discloses a method for synthesizing NDGA from a protected orthodihydroxybenzene. The patent claims a synthesis of racemic 2,3-dimethyl-1,4-bis(3,4-dialkoxyphenyl)1,4-butanedione. However the patent discloses the conversion of this diketone intermediary to 3,4-dimethyl-2,5-bis(3,4-dialkoxyphenyl)-furan, and from there through several routes to the final product NDGA.

US patent 3906004 claims a process for the preparation of NDGA by hydrogenating a hetrocyclic compound in the presence of palladium catalysts and inert solvents.

US patent 4562298 claims a process which involves conversion of optically active 1,4-bis (3,4-dimethoxyphenyl), 2, 3-dimethylbutane-1, 4-dione to 1,4-bis (3,4-dimethoxyphenyl), 2,3-dimethyl-butane-1, 4-diol by reduction, which is then methylated to form optically active molecules of 1, 4-bis (3,4-dimethoxyphenyl), 2, 3-dimethyl 1,4-dimethoxy-butane. The Optically active 1, 4-bis (3,4-dimethoxyphenyl), 2, 3-dimethyl-1, 4-dimethoxy-butane is then reacted to form 1, 4-bis (3,4-dimethoxyphenyl) 2, 3-dimethyl-butane which is eventually converted to NDGA. The process involves use of only optically active starting compounds to isolate the desired isomer.

Though research on NDGA is ongoing at a tremendous pace, the number of synthetic procedures reported for NDGA is limited in the literature. The reported synthetic known process suffer from drawbacks like lengthy and cumbersome reaction pathways, leading to tedious work ups and isolations of the intermediary compounds and the final product, thereby rendering the reactions as not viable at an industrial level. The above-cited references neither disclose the intermediates of the present invention nor the processes for their preparation; the preferred isomer is isolated by fractional crystallization, which is a simple and efficient route to isolate the NDGA in industrially quantitative yield. Thus the present inventors report a simple, facile, cost effective, high yielding and industrially viable synthesis of NDGA. The stage - wise synthesis of NDGA of the present invention is schematically represented below:

It has therefore been long felt need to develop process for synthesis of Nordihydroguaiaretic acid (NDGA, IV), which is chemical in nature and is pure and simple and cheaper.

These objects have been achieved by the process of the present invention which comprises of a process for the preparation of Nordihydroguaiaretic acid (NDGA, IV) of Formula V of the accompanying drawings which comprises reacting Ketone of formula 1 with 1,4 Dioxane to obtain compound of formula II and said compound of formula II is further reacted in presence of palladium/carbon to obtain compound of formula III which compound of formula III is taken and reacted in aqueous HBr to obtain compound of

Formula IV which if desired is subjected to fractional crystallization to obtain compound of formula V.
The reaction with 1, 4-dioxane is carried out in the presence of titanium chloride.
We shall now describe the invention with reference to the accompanying stages which are as under:

Stage I

Stage II

Stage III

Stage IV


In one embodiment of the invention, the ketone of the formula (i) 3, 4-dimethoxy propiophenone is converted to the alkene derivative of formula (ii) 1,4-bis (3, 4-dimthoxy phenyl)- 2, 3- dimethyl-but-2-ene. The conversion is mediated by the presence of Titanium chloride in 1,4 -dioxane. The reaction may be carried out in the presence of Titanium chloride, Diethylether, Benzene, Toluene, THF, DIBE. Titanium chloride being the most preferred coupling agent. The solvents that can be employed in the current stage are ether like 1,4,dioxane, THF, DIPE, DEE; wherein 1,4-dioxane being the most preferred.

In another embodiment of the invention, compound 1, 4-bis (3,4-dimthoxy phenyl)- 2, 3-dimethyl-but-2-ene is reduced to a novel compound (iii) 1, 4-bis (3,4-dimethoxy phenyl)-2, 3-dimethyl butane. The reducing agents that can be employed are Palladium / carbon, Ru/C, Pd/BaS04; Pd/C being the most preferred.

In yet another embodiment, the invention is directed to the dealkylation of compound of formula III to generate the corresponding racemic compound of NDGA of formula IV, which is subsequently subjected to fractional crystallization to isolate the preferred isomer.

In yet another object of the invention, the racemic NDGA is subjected to fractional crystallization by solvents like Acetic acid: H20, Acetonitrile, nitromethane, wherein acetic acid 75% is the most preferred.
The NDGA thus isolated is purified by recrystallization from solvents like acetonitrile, mixture of acetonitrile-water, acetonitrile acetic acid, acetic acid-water to obtain crystalline NDGA. Acetonitrile is the most preferred solvent for the recrystallization.

We shall now describe the present invention with reference to accompanying examples, which are given by way of illustrations but does not restrict the scope of the invention

Preparation of various varieties of Nordihydroguaiaretic acid Example 1:

Preparation of 1,4-bis (3,4-dimethoxy phenyl)- 2,3- dimethyl-but-2-ene To a stirred solution of 1,4-Dioxane 3880 L under N2 blanketing TiCI4 225 Kg was added at RT, the mass was slowly taken to 70°C followed by the addition of zinc dust 170 Kg (70° - 80°C, 4 hrs). The reaction contents were further stirred at 70° - 80°C for 1 1/2 hr and then at 90°C. The Ketone (I) 388.0 Kg was charged and the mass was taken to reflux for a period of 6hrs [check TLC, HPLC for the disappearance of (I)]. After recovering Dioxane (1940 L) under normal pressure, the mass was cooled to 40°C and water (3880 L) followed by 35% HCI (970 L) was slowly added. The contents were stirred for 1 hr and extracted with Carbon tetrachloride (3880 L) at RT. The Carbon tetrachloride layer was dried and distilled under atmospheric pressure and vacuum applied to remove traces of the solvent from the residue. To the residue, methanol (776.0 L) was charged and the mass cooled to 0-5°C. The crystalline contents were centrifuged and washed with cold methanol (200 L) to yield the desired 1,4-bis (3,4-dimthoxy phenyl)- 2,3- dimethyl-but-2-ene (284.8 Kg) [ 80% of Theory].

Example 2:

Preparation of 1,4-bis (3,4-dimethoxy phenyl)-2,3-dimethyl butane

To a clean stainless steel pressure reactor, methanol (4600 L) was charged followed by stage I compound (284.8 Kg). The system was flushed twice with N2 and then Pd/C 10% added under stirring (23.0 Kg). The reactor was sealed & the N2 released. The reactor contents were flushed twice with hydrogen and then pressurized to 7.0 Kg. The mass was then heated under stirring to 80°C and the pressure rise noted (~ 10.0 Kg).

The reaction was maintained at this temperature and pressure for 8 hrs& after HPLC in process check, the contents were cooled to 40°C followed by pressure release and N2 flushing. After the catalyst was filtered, methanol was distilled & fresh methanol (320 L) added to the mass. After cooling at 0-5°C the crystallized mass was centrifuged & washed with cold methanol to yield) 1,4-bis (3,4-dimethoxy phenyl)-2,3-dimethyl butane (214.8 Kg) [75% of Theory].

Example 3:
Preparation of Racemic 1,4-bis (3,4-dihydroxy phenyl)-2,3-dimethyl butane
HBr 47% (3200 L) was charged into a clean GLR under stirring followed by stage III (214.8 Kg), the mass temperature was taken to 120°C and maintained for 24 hrs, after checking the TLC/HPLC, the contents were cooled to RT and then 5°C, the mass was centrifuged and the cake washed with chilled water (200 L). The product was dried at 70°C for 24 hrs to yield the corresponding racemic mixture 1,4-bis (3,4-dihydroxy phenyl)-2,3-dimethyl butane (150.4 Kg) [83% of Theory].

Common examples for all varieties of Nordihydroguaiaretic acid
Example 4: Fractional Distillation
Acetic acid 75% (550 L) was charged in a clean GLR followed by stage IV (150.4 Kg) and active carbon (11.0 Kg) the reaction mass was refluxed for 1 hr, till complete dissolution and passed through a hiflo bed, to another GLR maintained at 0-5°C. The filtered mother liquors were further maintained at that temperature for a period of 3 hrs. After complete crystallization the product was centrifuged and washed with chilled water (110 L) to yield 87.0 Kg of wet cake, which was again taken for second fractional crystallization to yield the desired enriched isomer (V) in a yield of about 75.0 Kg.

Example 5:
Recrystallization of NDGA
Charge acetonitrile (300 L) in a glass reactor at RT and add stage V (75 Kg). The mass was heated to reflux for 45 minutes followed by charcoalizing and filtration through a hiflo bed. After cooling the mass to 0-5°C, the contents were centrifuged to yield about 70 Kg of wet cake. This process was repeated once more to obtain about 35.0 Kg of ultra-pure NDGA (V).

WE CLAIM:

1. A process for the preparation of Nordihydroguaiaretic acid (NDGA, IV) of Formula V of the accompanying drawings which comprises reacting Ketone of formula 1 with 1,4 Dioxane to obtain compound of Formula II and said compound of Formula II is further reacted in presence of palladium/carbon to obtain compound of Formula III which compound of Formula III is taken and reacted in aqueous HBr to obtain compound of Formula IV which if desired is subjected to fractional crystallization to obtain compound of Formula V.

2. A process as claimed in claim 1 wherein the reaction with 1,4-dioxane is carried out in the presence of titanium chloride.

3. A process as claimed in claim 1 wherein 1,4-bis (3,4-dimethoxy phenyl)- 2,3-dimethyl-but-2-ene is obtained as under:

to a stirred solution of 1,4-Dioxane 3880 L under N2 blanketing TiCI4 225 Kg was added at RT, the mass was slowly taken to 70°C followed by the addition of zinc dust 170 Kg (70° - 80°C, 4 hrs), the reaction contents were further stirred at 70° -80°C for 1 1/2 hr and then at 90°C, the Ketone (I) 388.0 Kg was charged and the mass was taken to reflux for a period of 6hrs [check TLC, HPLC for the disappearance of (I)], after recovering Dioxane (1940 L) under normal pressure, the mass was cooled to 40°C and water (3880 L) followed by 35% HCI (970 L) was slowly added, the contents were stirred for 1 hr and extracted with Carbon tetrachloride (3880 L) at RT, the Carbon tetrachloride layer was dried and distilled under atmospheric pressure and vacuum applied to remove traces of the solvent from the residue to the residue, methanol (776.0 L) was charged and the mass cooled to 0-5°C, the crystalline contents were centrifuged and washed with cold methanol (200 L) to yield the desired 1,4-bis (3,4-dimthoxy phenyl)- 2,3-dimethyl-but-2-ene(284.8 Kg) [ 80% of Theory].

4. A process as claimed in claim 1 wherein 1,4-bis (3,4-dimethoxy phenyl)-2,3-dimethyl butane is obtained as under:

a clean stainless steel pressure reactor, methanol (4600 L) was charged followed by stage I compound (284.8 Kg), the system was flushed twice with N2 and then Pd/C 10% added under stirring (23.0 Kg), the reactor was sealed & the N2 released, the reactor contents were flushed twice with hydrogen and then pressurized to 7.0 Kg, the mass was then heated under stirring to 80°C and the pressure rise noted (~ 10.0 Kg), the reaction was maintained at this temperature and pressure for 8 hrs& after HPLC in process check, the contents were cooled to 40°C followed by pressure release and N2 flushing, after the catalyst was filtered, methanol was distilled & fresh methanol (320 L) added to the mass, after cooling at 0-5°C the crystallized mass was centrifuged & washed with cold methanol to yield ) 1,4-bis (3,4-dimethoxy phenyl)-2,3-dimethyl butane(214.8 Kg) [75% of Theory],

5. A process as claimed in claim 1 wherein racemic 1,4-bis (3,4-dihydroxy phenyl)-
2,3-dimethyl butane is obtained as under:

HBr 47% (3200 L) was charged into a clean GLR under stirring followed by stage III (214.8 Kg), the mass temperature was taken to 120°C and maintained for 24 hrs, after checking the TLC/HPLC, the contents were cooled to RT and then 5°C, the mass was centrifuged and the cake washed with chilled water (200 L), the product was dried at 70°C for 24 hrs to yield the corresponding racemic mixture 1,4-bis (3,4-dihydroxy phenyl)-2,3-dimethyl butane (150.4 Kg) [83% of Theory]

6. A process as claimed in any of claims 1 to 5 wherein Fractional Distillation is carried out as under:
acetic acid 75% (550 L) was charged in a clean GLR followed by stage IV (150.4 Kg) and active carbon (11.0 Kg) the reaction mass was refluxed for 1 hr, till complete dissolution and passed through a hiflo bed, to another GLR maintained at 0-5°C,the filtered mother liquors were further maintained at that temperature for a period of 3 hrs, after complete crystallization the product was centrifuged and washed with chilled water (110 L) to yield 87.0 Kg of wet cake, which was again taken for second fractional crystallization to yield the desired enriched isomer (V) in a yield of about 75.0 Kg.

7. The process as claimed in any one of claims 1 to 6 wherein recrystallization of NDGA is carried out as under:

acetonitrile (300 L) was charged in a glass reactor at RT and at stage V (75 Kg), -the mass was heated to reflux for 45 minutes followed by charcoalizing and filtration through a hiflo bed, after cooling the mass to 0-5°C, the contents were centrifuged to yield about 70 Kg of wet cake, process was repeated once more to obtain about 35.0 Kg of ultra-pure NDGA (V).