Title of Invention

PROCESS FOR MANUFACTURE OF WATER-SOLUBLE CINNAMIDOPROPYL TRIMETHYL AMMONIUM TOSYLATES

Abstract A process for preparing water-soluble, cinnamidopropyl trimethyl ammonium tosylates of Formula I, wherein; R1 is a substituent, selected from H, halo, -OH, -NH2, -N02, -OCH3, -N(CH3)2, alkyl groups containing from 1 to 6 carbon atoms, alkoxy groups containing from 1 to 6 carbon atoms, alkylamino or N,N-dialkylamino groups containing from 1 to 6 carbon atoms; comprising steps of i) reacting 1.0 mole of a compound of Formula II, wherein, R1 is same as that in the compound of said Formula I that is being synthesized, and R2 is , -OH, -CI, -0(CH2)PCH3 (p=0 to 3) or an alkyl group with 1 to 4 carbon atoms, with 1.0 to 3.0 moles of N,N-dimethyl propyl diamine, with or without solvent, with or without a basic catalyst, to obtain a compound of Formula HI, wherein, R1 is same as that for the compound of said Formula I that is being synthesized, till all of the said compound of Formula II has been reacted, the remaining unreacted N,N-dimethyl propyl diamine and the solvent were removed to obtain the said compound of Formula HI; ii) carrying out quaternisation on said cinnamidopropyl dimethyl amine of Formula HI obtained at the end of step (i) with 1.0 mole of methyl tosylate by stirring under nitrogen, at about 85 to 100°C, in the presence of protic solvents from about 30 % to 80 % by weight of the reaction mass until unreacted cinnamidopropyl dimethyl amine level in the reaction mass reaches less than 0.5 %.
Full Text FORM 2
THE PATENTS ACT, 1970
(39 of 1970
COMPLETE SPECIFICATION
(See Section 10 : Rule 13)
TITLE
Process for manufacture of water-soluble cinnamidopropyl trimethyl ammonium tosylates
APPLICANT
Galaxy Surfactants Ltd.,
C-49/2, TTC Industrial Area, Pawne, Navi-Mumbai 400 703, Maharashtra, India.
A Public Limited Company Registered under Indian Company's Act - 1956
The following specification particularly describes the nature of this invention and the manner in which it is to be performed :-

ORIGINAL
640/MUM/2002
12/7/02

GRANTED
18-12-2003





Field of Invention :
This invention relates to a process for manufacture of cinnamidopropyl trimethyl ammonium tosylates that are non-hydrolyzable, non-irritant and substantive to skin, hair and fabric.
Background and Prior Art:
The harmful effects of solar UV-radiation on skin are well known. The UV-B (290 - 320 nm) portion of solar spectrum is largely responsible for erythema (sunburn) and cancer. [M. M. Rieger, Cosmet. Toiletries, 102 (3), 91, (1987); L. Taylor, Skin Cancer Foundation J., 4, (90) (1986)].
Similarly, photodegradative effect of UV-radiation on human hair is well documented. Continuous exposure to sunrays makes human hair color and makes human hair rough, brittle and difficult to comb. UV rays are reported to damage the proteins of cuticles. Prolonged irradiation results in diminished tensile strength due to breaking of disulphide bonds in keratin. [R. Beyak et al, J. Soc. Cosmet. Chem. 22, 667 - 668 (1971), E. Hoting et al, J. Soc. Cosmet. Chem. 46, 85-99 (1995)]
In addition, UV light is also known to fade garments. [P. C. Screws, Text. Chem. Color, 11, 21 (1987); B. Milligan et al, Polym. Degrad. Stab. 10 (4), 335 (1985)]
A number of UV-absorbing compounds like derivatives of salicylic acid, benzophenones, benzotriazoles, cinnamic acid have been used in personal care products. However, all these molecules suffered from a major disadvantage of lack of substantivity. To make this UV-absorbing moieties more substantive, structural modification have been introduced. For example, US patent 5,601,811 (1997) describes substantive UV-absorbing quaternary ammonium compounds containing cinnamidoalkylamine and product compositions for detergents, household cleaners and personal care products. However, the counter anions of the quaternaries described in this patent are not ideally suitable for skin care applications. Tosylate as a counter ion is reported to be much softer and non-irritating to the skin [P. J. Petter, Soaps, Cosmetics & Perfumery, pg. 29 - 34, March 1997]. In addition to the mildness that it offers, the tosylate anion also contributes to higher UV-absorbing property of the quaternary compound. Hence, the compounds of the present invention are designed to address the need for high water solubility as well as non-irritancy arising out of tosylate anion for this class of substantive sunscreen molecules.
Object of the invention :
The main object of the present invention is therefore to synthesize water-soluble, substantive molecules with cinnamido moiety with tosylate as counter anion for the desired softness to skin.

Summary of the invention :
The present invention provides a process for the preparing novel, cinnamidopropyl trimethyl ammonium tosylates of Formula I,

wherein;
R1 is a substituent, selected from H, halo, -OH, -NH2, -NO2, -OCH3, -N(CH3)2, alkyl groups containing from 1 to 6 carbon atoms, alkoxy groups containing from 1 to 6 carbon atoms, alkylamino or N,N-dialkylamino groups containing from 1 to 6 carbon atoms;
comprising steps of
i) reacting 1.0 mole of a compound of Formula n, wherein, R1 is same as that in the compound of said Formula I that is being synthesized, and R2 is , -OH, -CI, -0(CH2)PCH3 (p=0 to 3) or an alkyl group with 1 to 4 carbon atoms, with 1.0 to 3.0 moles of N,N-dimethyl propyl diamine, with or without solvent, with or without a basic catalyst, to obtain a compound of Formula HI, wherein, R1 is same as that for the compound of said Formula I that is being synthesized, till all of the said compound of Formula II has been reacted, the remaining unreacted N, N-dimethyl propyl diamine and the solvent were removed to obtain the said compound of Formula HI;

ii) carrying out quaternisation on said cinnamidopropyl dimethyl amine of Formula III obtained at the end of step (i) with 1.0 mole of methyl tosylate by stirring under nitrogen, at about 85 to 100°C, in the presence of protic solvents from about 30 % to 80 % by weight of the reaction


mass until unreacted cinnamidopropyl dimethyl amine level in the reaction mass reaches less than 0.5 %.
Detailed description of the invention :
The process for preparing cinnamidopropyl trimethyl ammonium tosylates of the present invention involves two steps, namely, amidification and quatemisation. In the process, the amidification reaction between a compound of the Formula II when R2 = -OH or -0(CH2)PCH3 (p = 0 to 3), withN,N-dimethyl propyl diamine is carried out at from about 120°C to about 200°C, under pressure from about 10 psi to about 100 psi, in the presence of a basic catalyst such as sodium methoxide, sodium hydroxide from 0.25 % to 5.0 % by weight of the reaction mass, to afford the intermediate compound of Formula HI.
From about 0.5 % to 5.0 % w/w of the basic catalyst should be employed. Preferred amount of such catalyst is 1.0 % w/w of total reaction mass. The reaction is conveniently monitored by TLC or HPLC using UV detection. After the complete disappearance of cinnamic acid ester, the excess diamine is distilled off under vacuum.
Alternately, this reaction is carried out in the presence of a basic catalyst such as sodium methoxide, sodium hydroxide from 0.25 % to 5.0 % by weight of the reaction mass under atmospheric pressure, under blanket of nitrogen, with an arrangement for continuous selective removal of lower alcohol formed in the reaction.
Thus, the condensation reaction of one mole of cinnamic acid ester is carried with 1.0 to 3 moles of diamine at 120 to 200°C, preferably at 180°C, for 12 to 36 hours. The amine itself can catalyse the reaction, however, the rate is found to be slower as compared with the bases like sodium methoxide and the like.
The same reaction can be performed using cinnamic acid in place of cinnamic acid ester at temperatures up to 200°C and pressures of 100 psi, keeping the same stoichiometry (1 : 1.0 to 3). The excess diamine serves as solvent for the reaction.
The amidification reaction between a compound of Formula II when R2 = -CI is carried out with N,N-dimethyl propyl diamine at room temperature in the presence of solvent. The compounds of Formula HI are synthesised by reacting acid chlorides of Formula II (1.0 mole) when R2 is -Cl

with N,N-dimethyl propyl diamine (1.0 to 1.2 mole) at 20 - 50°C in an inert solvent like dichloromethane, ethylene dichloride, tetrahydrofuran and the like.
The alkylating agent used in present invention is methyl tosylate that is in turn synthesised from tosyl chloride and methanol. Quaternization of cinnamidoamines is carried out with methyl tosylate without or with solvents that include isopropanol and f-butanol. Solvents used are from 20 to 80 % by weight of the reaction mass. The cinnamidoalkylamines (Formula III1.0 mole) are N-alkylated with methyl tosylate in the presence of suitable solvents like f-butanol or isopropanol that govern the temperatures at which the reaction is carried out. Quaternisation can also be carried out without solvents by simply heating equivalent quantities of compounds of Formula II and methyl tosylate at 100 - 130°C.
In another embodiment the process of the present invention relates to manufacture of compounds of Formula I, in which R1 is selected from H, -OH, halogen, N,N-dialkylamino groups containing from 1 to 6 carbon atoms, alkoxy groups containing from 1 to 6 carbon atoms; from the compounds of Formula II, N,N-dimethyl propyl diamine and methyl tosylate, with respective substituents R1 of Formula II and R2 of Formula II being -OH, -CI, -Br or -0(CH2)pCH3 (p = 0 to 3).
In another embodiment the process of the present invention relates to manufacture of a compound of Formula I, in which R1 = para -OCH3, from compound of Formula II (p-methoxy ethyl cinnamate, R1 = -OCH3, R2 = -OC2H5), N,N-dimethyl propyl diamine to form an intermediate compound of Formula HI (p-methoxy cinnamidopropyldimethyl amine, R1 = -CH3) and methyl tosylate. The process of preparation of such compounds is given in Example I.
In another embodiment the process of the present invention relates to manufacture of a compound of Formula I, in which R1 = para -OCH3, from compound of Formula II (p-methoxy cinnamoyl chloride, R1 = -OCH3, R2 = -CI), N,N-dimethyl propyl diamine forming an intermediate compound of Formula III (p-methoxy cinnamidopropyldimethyl amine, R1 = -OCH3) and methyl tosylate. The process of preparation of such compounds is given in Example
II
In these quaternary compounds as shown in Formula I, the ring is either unsubstituted or contains one substituent more preferably in para position. R1 is selected from moieties such as -H, -halo, -OH, -NH2, -N02, -OCH3, -N(CH3)2 on the phenyl ring.
Thus, the cinnamidopropyl trimethyl ammonium tosylates of the present invention are formed by quaternising compounds of Formula HI by methyl tosylate. Given the quaternizing agent described above, the quaternary type of compounds of the present invention of Formula I will contain a positively charged nitrogen and a negatively charged tosylate anion.
Examples

The invention will now be illustrated with the help of examples. The examples are by way of illustrations only and in no way restrict the scope of the invention.
Example I
N,N-dimethyl propyldmine was obtained from BASF. Ethyl p-methoxy cinnamate and p-methoxy cinnamoyl chloride were supplied by Galaxy Surfactants Ltd., Mumbai.
Process for preparation p-methoxy cinnamidopropvl trimethvl ammonium tosylate : The compound of Formula I, wherein, R1 = -OCH3.
p-Methoxy cinnamidopropyldimethylamine was synthesised from ethyl p-methoxy cinnamate and N,N-dimethylpropyldiamine.
a) Preparation of p-methoxy cinnamidopropyldimethylamine :
Ethyl p-methoxy cinnamate (206.0 g, 1.0 mole),N,N-dimethylpropyldiamine (306.0 g, 3.0 mole) and sodium methoxide (2.0 g) were charged in a pressure reactor. The air inside the reactor was flushed out by purging of nitrogen. The reaction mixture was then stirred at 180°C (this generated pressure of 18 kg / cm2) for 36 hours. The progress of reaction was monitored by disappearance of ethyl p-methoxy cinnamate on chromatography (TLC and HPLC). The TLC was performed on aluminium coated silica gel plates (Merck - 60-F-254) and viewed with a UV lamp at 254 nm. HPLC was performed using reversed phase technique on a C-18 bonded (octadecyl silane) column and 60 % aqueous methanol as mobile phase (1.0 ml / min) and detection at 280 nm. The excess amine was removed under vacuum. The golden yellow solid (263.0 g) thus obtained had amine value of 245. Molar extinction coefficient, e, in methanol was found to be 24,224 at 290 nm.
IR in dichloromethane showed carbonyl stretching of amide at 1660 cm'1 and NH stretching at 3300 cm'1.
1H NMR (300 MHz, CDCI3) : 8 1.73 (p, 2H, J = 6.6 Hz), 2.26 (s, 6H), 2.42 (t, 2H, J = 6.6 Hz), 3.45 (q, 2H, J = 6.0 Hz), 3.81 (s, 3H), 6.27 (d, 1H, J = 15.6 Hz), 6.86 (d, 2H, J = 8.7 Hz), 7.43 (d, 2H, J = 8.7 Hz), 7.53 (d, 1H, J = 15.6 Hz).
b) Quaternisation of p-methoxy cinnamidopropvl dimethyl amine with methyl tosylate : p-Methoxy cinnamidopropyldimethyl amine (36.0 g, 374 mmoles) was charged in a stainless steel pressure reactor along with methyl tosylate (24.25 g, 130 mmoles) and isopropanol (140 ml). The reaction mixture was stirred under nitrogen pressure of 0.5 kg / cm2 at 85 - 90°C. The reaction was monitored by estimation of unreacted cinnamidoalkylamine. Isopropanol removal yielded viscous mass that was redissolved in water to give 50 % solution.
1H NMR (D20, 300 MHz): 8 1.95 (m, 2H), 2.31 (s, 3H), 2.86 (s, 6H), 3.06 (s, 3H), 3.12 (m, 2H), 3.33 (m, 2H), 3.78 (s, 3H), 6.35 (d, 1H, J = 15.6 Hz), 6.90 (d, 2H, J = 8.7 Hz), 7.27 (d, 2H, J = 8.0 Hz), 7.36 (d, 1H, J = 15.6 Hz), 7.45 (d, 2H, J = 8.7 Hz), 7.65 (d, 2H, J = 8.4 Hz).

The molar extinction coefficient,E was found to be 25,864 at nax 308 nm in water.
Example II
Process for preparation p-methoxy cinnamidopropvl trimethyl ammonium tosylate : The compound of Formula I, wherein, R1 = -OCH3.
(a) Preparation of p-methoxy cinnamidopropyldimethylamine :
To a stirred solution of N,N-dimethylpropyldiamine (102.0 g, 1.0 mole) in dichloromethane (500
ml), solution of p-methoxy cinnamoyl chloride (196.0 g, 1.0 mole) in dichloromethane from step
(a) was slowly added and the reaction was continued at room temperature for 2 hours. The
reaction mixture in dichloromethane was washed with aqueous sodium hydroxide (200 ml, 20.0
%). The organic layer was dried over anhydrous sodium sulphate. The removal of solvent using
a rotary evaporator afforded the p-methoxy cinnamidopropyldimethylamine (235.0 g) as
colourless solid, m.p. 80°C. Reversed phase HPLC showed it to be 98 % pure with amine value
217.
The NMR and IR data matched with the data for the compound obtained in Example I (a).
(b) Quaternisation of p-methoxy cinnamidopropyldimethylamine with methyl tosvlate :
The preparation was carried out as per the experiment described in Example I (b).
The NMR, UV data matched with the data obtained in Example I (b).
A process for preparing water-soluble, cinnamidopropyl trimethyl ammonium tosylates of general Formula I, from substituted propyl dimethyl cinnamidoalkylamines and methyl tosylate, substantially as herein described, in the text and in the examples.

Advantages of the process :
The process of the present invention gives cinnamidopropyl trimethyl ammonium tosylates having high water solubility, substantivity and sunscreen properties that are useful for personal care and fabric care products. The process of the present invention gives a product in solution form and is convenient to use in the formulation directly.
The biggest advantage of cinnamidopropyl trimethyl ammonium tosylates of the present invention is that they are higher UV-absorbing and milder to skin by virtue of having tosylate as counter anion as compared to water-soluble quaternaries based on cinnamido moiety described in the prior art.

We claim
1. A process for preparing water-soluble, cinnamidopropyl trimethyl ammonium tosylates of Formula I,

wherein;
R1 is a substituent, selected from H, halo, -OH, -NH2, -N02, -OCH3, -N(CH3)2, alkyl groups containing from 1 to 6 carbon atoms, alkoxy groups containing from 1 to 6 carbon atoms, alkylamino or N,N-dialkylamino groups containing from 1 to 6 carbon atoms;
comprising steps of
i) reacting 1.0 mole of a compound of Formula II, wherein, R1 is same as that in the compound of said Formula I that is being synthesized, and R2 is , -OH, -CI, -0(CH2)PCH3 (p=0 to 3) or an alkyl group with 1 to 4 carbon atoms, with 1.0 to 3.0 moles of N,N-dimethyl propyl diamine, with or without solvent, with or without a basic catalyst, to obtain a compound of Formula HI, wherein, R1 is same as that for the compound of said Formula I that is being synthesized, till all of the said compound of Formula II has been reacted, the remaining unreacted N,N-dimethyl propyl diamine and the solvent were removed to obtain the said compound of Formula HI;

ii) carrying out quaternisation on said cinnamidopropyl dimethyl amine of Formula HI obtained at the end of step (i) with 1.0 mole of methyl tosylate by stirring under nitrogen, at about 85 to 100°C, in the presence of protic solvents from about 30 % to 80 % by weight of the

reaction mass until unreacted cinnamidopropyl dimethyl amine level in the reaction mass reaches less than 0.5 %.

2. A process as claimed in claim 1, wherein, is manufactured compound of Formula I, p-methoxy cinnamidopropyl trimethyl ammonium tosylate, in which R1 = para -OCH3, from compound of Formula II (p-methoxy ethyl cinnamate, R1 = -OCH3, R2 = -OC2H5), N,N-dimethyl propyl diamine forming an intermediate compound of Formula HI (p-methoxy cinnamidopropyldimethyl amine, R1 = -OCH3) and methyl tosylate.
3. A process as claimed in claim 1, wherein, is manufactured compounds of Formula I, p-methoxy cinnamidopropyl trimethyl ammonium tosylate, in which R1 = para -OCH3, from compound of Formula II (p-methoxy cinnamoyl chloride, R1 = -OCH3, R2 = -CI), N,N-dimethyl propyl diamine forming an intermediate compound of Formula HI (p-methoxy cinnamidopropyldimethyl amine, R1= -OCH3) and methyl tosylate.
4. A process for preparing water-soluble, cinnamidopropyl trimethyl ammonium tosylates of general Formula I, from substituted propyl dimethyl cinnamidoalkylamines and methyl tosylate, substantially as herein described, in the text and in the examples.
Dated this 11th day of July, 2002.
(Shanbhag Shashikant) Galaxy Surfactants Limited. C-49/2, TTC Industrial Area, Pawne, Navi Mumbai - 400 703 (Applicant)

Indian Patent Application No. 640 / Mum / 2002. Galaxy Surfactants Limited.

One sheet Sheet No.2

Documents:

640-mum-2002-cancelled pages(18-12-2003).pdf

640-mum-2002-claims(granted)-(18-12-2003).doc

640-mum-2002-claims(granted)-(18-12-2003).pdf

640-mum-2002-correspondence(18-12-2003).pdf

640-mum-2002-correspondence(ipo)-(26-10-2006).pdf

640-mum-2002-form 1(12-7-2002).pdf

640-mum-2002-form 19(24-6-2003).pdf

640-mum-2002-form 2(granted)-(18-12-2003).doc

640-mum-2002-form 2(granted)-(18-12-2003).pdf

640-mum-2002-form 3(18-12-2004).pdf


Patent Number 203114
Indian Patent Application Number 640/MUM/2002
PG Journal Number 15/2007
Publication Date 13-Apr-2007
Grant Date 26-Oct-2006
Date of Filing 12-Jul-2002
Name of Patentee GALAXY SURFACTANTS LIMITED
Applicant Address GALAXY SURFACTANTS LIMITED, C-49-2, TTC INDL. AREA, PAWNE, NAVI MUMBAI - 400 703,
Inventors:
# Inventor's Name Inventor's Address
1 KOSHTI NIRMAL AND NAIK SHUBHANGI GALAXY SURFACTANTS LIMITED, C-49/2, TTC INDL. AREA, PAWNE, NAVI MUMBAI-400 703,
PCT International Classification Number N/A
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA