The present invention relates to a process for the preparation of propranolol hydrochloride of Formula I

Formula I
BACKGROUND OF THE INVENTION
Propranolol hydrochloride is sold under the trade name Inderal. Propranolol hydrochloride chemically known as l-(l-naphthoxy)-3-isopropylamino-2-propanol hydrochloride, represented by Formula I, is used in the prevention and treatment of arrhythmia, angina pectoris, hypertension, myocardial infarction, coronary heart disease, hyperthyroidism etc.

Formula I
US 3,337,628 describes a process for the preparation of propranolol hydrochloride by reacting 2-epoxy-3 -naphthoxypropane and isopropyl amine under reflux condition. Propranolol free base is converted into its hydrochloride salt in acetone and ION HC1 followed by the crystallisation in propanol.
GB 2238786 B, describes a process for the preparation of propranolol hydrochloride by reaction between 1-naphthol and epichlorohydrin in the presence of triethylamine as catalyst, wherein a major side product of the reaction is l-(l-naphthoxy)-3-chloropropan-2-ol. This side product, however, can be substantially converted to the desired intermediate of the reaction, i.e. l-(l-naphthoxy)-2,3-epoxypropane, by treatment of the product mixture with sodium hydroxide. Process as disclosed in

GB'786 results in the formation of many impurities which affects the overall yield. Also, said process involves the use of magnesium trisilicate along with hyflow supercell in toluene as a solvent, which makes the process cumbersome and expensive.
GB 1079534 A, describes a process for the preparation of propranolol hydrochloride by heating the reaction mixture containing 1-naphthol, epichlorohydrin, isopropyl amine, sodium hydroxide and ethanol at 100°C for 10 hours.
IN 2071/DEL/2012, describes a process for the preparation of propranolol by reacting benzylated isopropylamine with epichlorohydrin followed by reaction with (2-[(l-naphthyloxy)methyl]oxirane). The process involves several protecting and de-protecting steps making the said process highly expensive to be followed at large scale production..
Journal of the Serbian Chemical Society 2006 Volume 71, Issue 8-9: 867-877\ describes a process of propranolol by reacting 1 -naphthol with epichlorohydrin in the presence of PTC (tetrabutylammonium bromide) which is an expensive reagent. ^
IN 2643/DEL/2015, describes a process for the preparation of propranolol by heating a mixture of 1-naphthol, epichlorohydrin and triethylamine at 60°C for 5 hours followed by adding cone. HC1 and further reacted for 3 hours that results in the formation of undesired products along with the desired propranolol.
The processes as described in prior published references, result with a product having many impurities, which impacts the overall yield. Also, the work up processes as disclosed in the prior references are more cumbersome, tedious and time consuming. To avoid the above stated drawbacks, present invention provides a simple and cost effective process for preparation of propranolol hydrochloride wherein, the workup and isolation of product is simple as compared to the processes disclosed in prior published references.

OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved, cost effective and environment friendly process for the preparation of propranolol hydrochloride of Formula I.
SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide an improved process for the preparation of propranolol hydrochloride of Formula I,

Formula I
wherein said process comprising the steps of:
a) refluxing 1 -naphthol compound of Formula II with epichlorohydrin compound of Formula III in presence of a base to obtain a reaction mixture
comprising the compounds of Formula IV and V


O
Base
°^ci

Formula V
Formula IV
Formula II
Formula III
b) treating the reaction mixture of step a) with aq. sodium hydroxide to get the compound of Formula IV




Aq. NaOH

Formula IV Formula V

Formula IV.

c) treating the compound of Formula IV with isopropyl amine to obtain propranolol free base of Formula VI

O ' " . .
NH-


Formula IV

Formula VI

d) treating the propranolol free base of Formula VI with acetone and aq. hydrochloric acid



Acetone Aq. HCI

Formula VI

Formula I

; and

e) isolating the propranolol hydrochloride of Formula I.
The other aspect of the present invention is to provide an improved process for the preparation of propranolol hydrochloride of Formula I,

Formula I
wherein said process comprising the steps of:

a) refluxing 1-naphthol compound of Formula II with epichlorohydrin compound of Formula III in the presence of N,N-diisopropylethylamine (DIPEA) to obtain a reaction mixture comprising the compounds of Formula
IV and V




* °^ci

DIPEA

Formula II

Formula III

Formula IV

Formula V

b) treating the reaction mixture of step a) with aq. sodium hydroxide to get the compound of Formula IV

O v-0
Aq. NaOH

Formula IV

Formula V

Formula IV.


c) treating the compound of Formula IV with isopropyl amine to obtain Propranolol free base of Formula VI 0
NH-


Formula IV

Formula VI

d) treating the propranolol free base of Formula VI with acetone and aq. hydrochloric acid



Acetone Aq. HCI

Formula VI

Formula I

; and

-CH*. FCO --^Sf- CM
* - " T. — ■■- . — .-^ 4-M -i*w esc »•

e-F-'

e) isolating the propranolol hydrochloride of Formula I.
The one another aspect of the present invention provides a one pot-process for the preparation of propranolol free base of Formula VI,

Formula VI
wherein said process comprising of:
a) refluxing 1-naphthol of Formula II with epichlorohydrin of Formula III in presence of N,N-diisopropylethylamine for 2-3 hours at 110-115°C and obtaining a reaction mixture comprising the compounds of Formula IV and Formula V;
b) adding 50% aq. sodium hydroxide solution to the reaction mixture of step a) at room temperature for 5-6 hours and producing a reaction mixture comprising (2-[(l-Naphthyloxy)methyl]oxirane) of Formula IV;
c) adding isopropyl amine to the reaction mixture of step b) at 10-15°C followed by stirring at 55-60°C for 12-15 hours;
d) extracting the reaction mixture of step c) with organic solvent and water; and
e) isolating the propranolol free base of Formula VI.
DETAILED DESCRIPTION
Brief Description of the accompanying drawing
Fig. 1, represents the X-ray (powder) diffraction (XRPD) pattern of the crystalline
form of Propranolol hydrochloride of Formula I.
Fig. 2, represents the Differential Scanning Calorimetry (DSC) pattern of the
crystalline form of propranolol hydrochloride of Formula I.
I***--: 1^?—t@-a#TO: ypT:* &W-"'

In one embodiment, the present invention provides an improved process for the preparation of propranolol hydrochloride of Formula I,

Formula I
wherein said process comprising the steps of:
a) refluxing 1-naphthol compound of Formula II with epichlorohydrin
compound of Formula III in the presence of a base to obtain a reaction
mixture comprising the compounds of Formula IV and V


O
Base
♦ °L>WCI

Formula II

Formula III

Formula IV

Formula V

b) treating the reaction mixture of step a) with aq. sodium hydroxide to get the of Formula IV

0 Vo
Aq. NaOH

Formula IV

Formula V

Formula IV.

c) treating the compound of Formula IV with isopropyl amine to obtain propranolol free base of Formula VI
m? ■■■•' t" ^ i-B-~'^B^8iv'' FF -?W?'
8




NH-


Formula IV

Formula VI

d) treating the propranolol free base of Formula VI with acetone and aq, hydrochloric acid to obtain propranolol hydrochloride of Formula I



Acetone Aq. HCI

Formula VI

Formula I

; and

e) isolating the propranolol hydrochloride of Formula I.
In other embodiment, the base used in step a) is selected from diisopropyl ethyl amine (DIPEA), DBU (l,8-diazabicyclo[5.4.0]undec-7-ene), triethyl amine, dicyclohexyl amine. The preferred bases are DIPEA and DBU and the most preferred base used in step a) is DIPEA.
In one other embodiment, the present invention provides an improved process for the preparation of propranolol hydrochloride of Formula I,


Y

Formula I
wherein said process comprising of:
a) refluxing 1-naphthol compound of Formula II with epichlorohydrin compound of Formula III in the presence of N,N-diisopropylethylamine (DIPEA) to obtain
>.v •w-±<>*tt~&>&x^:*% F:='€^?c

a reaction mixture comprising the compounds of Formula IV and Formula V

O

DIPEA ^^-k^ +
Formula II
Formula III
Formula IV Formula V

b) treating the reaction mixture of step a) with aq. sodium hydroxide to get the
compound (2-[(l-naphthyloxy)methyl]oxirane) of Formula IV
O ^O
Aq. NaOH

Formula IV Formula V Formula IV.
c) treating the compound of Formula IV with isopropyl amine to obtain

propranolol free base of Formula VI 0
NH-


Formula IV

Formula VI

d) treating the propranolol free base of Formula VI with acetone and aq. hydrochloric acid;




N H
o*

Formula VI

OH

Acetone Aq. HCI

O'
Formula I

OH

.HCI

; and

e) isolating the propranolol hydrochloride of Formula I.

1 T - I. C|.- ■> (\-V ft T 7- 1 A-7
%t\\j ™L3IP' KTtS "tSJ" ^

10

In another embodiment, the present invention provides a one-pot process for the preparation of propranolol free base of Formula VI,

Formula VI
wherein said process comprising of:
a) refluxing 1-naphthol of Formula II with epichlorohydrin of Formula III in presence of N,N-diisopropylethylamine for 2-3 hours at 110-115°C and obtaining a reaction mixture comprising the compounds of Formula IV and Formula V;
b) adding 50% aq. sodium hydroxide solution to the reaction mixture of step a) at room temperature for 5-6 hours and producing a reaction mixture comprising (2-[(l-naphthyloxy)methyl]oxirane) of Formula IV;
c) adding isopropyl amine to the reaction mixture of step b) at 10-15°C followed by stirring at 55-60°C for 12-15 hours;
d) extracting the reaction mixture of step c) with organic solvent and water; and
e) isolating the propranolol free base of Formula VI.
In yet another embodiment the organic solvent used in step d) for extraction is selected from toluene, dichloromethane and ethyl acetate, and the most preferred solvent used for extraction in step d) is toluene.
ii

Scheme 1: One pot synthesis of propranolol free base of Formula VI:

0

■0

OH

Formula II

+ L^-/ DIPEA
Formula III

*0

o' ^r xi
OH
Formula IV Formula V

Aq. NaOH

*o

Formula IV

NH-


O' y 'N-OH H

Formula VI
In one embodiment, propranolol hydrochloride of Formula I obtained in the present invention is crystalline in nature.
In one another embodiment, propranolol hydrochloride of Formula I obtained in present invention may be amorphous in nature.

CD G)
Q.
CD
E o

In one another embodiment propranolol hydrochloride of Formula I is characterized by its XRPD having peaks at diffraction angles 2-theta of 8.30, 9.69, 12.41, 12.77, 13.53, 14.42, 16.66, 17.15, 18.54, 19.42, 19.83, 21.16, 22.00, 22.19, 22.98, 23.53, 24.00, 24.99, 25.32, 25.73, 26.30, 26.98, 27.36, 27.75, 28.91, 29.83, 29.55, 30.50, 31.29, 31.96, 32.41, 32.91, 33.54, 33.82, 34.91, 35.64, 36.59, 36.87, 37.96 and 38.98 ±0.2° 29.
In yet another embodiment propranolol hydrochloride of Formula I is characterized by its XRPD as depicted in Fig-1.

In one another embodiment propranolol hydrochloride of Formula I is characterized by its DSC curve having endothermic peak at 164.98°C as depicted in Fig-2.

o

t T - i ft- - ■> n-i st i- 7 : 8-7

12

In another embodiment, the present invention provides a substantially pure , amorphous form of propranolol hydrochloride of Formula I, wherein said amorphous form is substantially free of any crystalline form.
In a preferred embodiment, the present invention provides a substantially pure crystalline form of propranolol hydrochloride of Formula I.
In other embodiment, the present invention provides propranolol hydrochloride of Formula I, wherein propranolol hydrochloride of Formula I is the mixture of amorphous and crystalline form.
In a preferred embodiment, the propranolol hydrochloride of Formula I may be isolated from the reaction mixture by purification, centrifugation, crystallization, filtration, extraction or evaporation.
In furthermore embodiment, the present invention provides a substantially pure propranolol hydrochloride of Formula I, wherein said propranolol hydrochloride of Formula I is substantially free of impurities of Formula A, B, C and D, and wherein each impurity is less than about 0.15% w/w or total impurity is less than about 1% w/w, more specifically less than about 0.15% w/w of any impurity
^

• *V Z7. _f !l L, i if' _m'/;iirr "" i-r-•'■——■—tura-i-w-

<">•' ?•*

13

Formula A Formula B


Formula C Formula D
The major advantage of the process of the present invention is using N,N-diisopropylethylamine as a base in the step of condensation of 1-naphthol of Formula II with epichlorohydrin of Formula III followed by conversion to propranolol hydrochloride wherein said propranolol hydrochloride so obtained is substantially free of impurities of Formula A, B, C and D.
In further embodiment, the present invention provides propranolol hydrochloride of Formula I characterized by particle size distribution wherein, d9o is between 0.1 |im to 200|im.
In a preferred embodiment, the propranolol hydrochloride of Formula I is characterized by particle size distribution wherein, d90 is between 2.0 ^m to 150|im.
In one another embodiment, the propranolol hydrochloride of Formula I prepared as per the process of the present invention is characterized with purity above 99%, preferably above 99.5%, and more preferably above 99.9%.
In a preferred embodiment, the present invention provides a substantially pure crystalline form of propranolol hydrochloride of Formula I, wherein said crystalline form is substantially free of amorphous form.


In one another embodiment, the present invention further provides a composition comprising propranolol hydrochloride of Formula I prepared by the process of present invention along with one or more pharmaceutical acceptable excipients.
The present invention can be illustrated by the following examples, which are not to limit the scope of invention.
EXAMPLES
Example-l: Synthesis of (2-[(l-naphthyIoxy)methyI]oxirane) of Formula IV
To a 1.0 L, three-necked round bottom flask fitted with condenser and temperature probe on a mechanical stirrer was charged epichlorohydrin (70.65g, 0.763 moles, 2.2 eq), 1-naphthol (50.Og, 0.347 moles, 1.0 eq.) and catalytic amount of N,N-diisopropylethylamine (8.97 g, 0.069 moles, 0.2 eq.). The resultant mixture was heated to 110-115°C and was allowed to stir at same temperature for 2-3 hours. After completion of the reaction, as monitored by HPLC, the mixture was distilled at 90°C under vacuum to recover epichlorohydrin and then cooled to 25-30°C. 50% aq. NaOH solution (13.88g, 0.347 moles, 1.0 eq.) was added to the above oily material and stirred the mass for 5-6 hours at 20-25°C for complete conversion of l-chloro-3-(l-naphthoxy)-2-propanol of Formula V to (2-[(l-naphthyloxy) methyl] oxirane) of Formula IV. After complete conversion, toluene (500 ml) and DM water (500 ml) was charged to the above suspension and stirred for 15 min for layer separation. Water layer was extracted with 500 ml toluene. Toluene layer was washed with 500 ml DM water followed by 500 ml brine solution. The resultant toluene layer was treated with 5% activated carbon followed by distillation and degassing to obtain compound of Formula IV as reddish-brown oily material (55.3 g, 79.6% yield, -92% on HPLC).
Example-2: Synthesis of (2-[(l-naphthyloxy)methyl]oxirane) of Formula IV
15

Charged epichlorhydrin (70.62g, 0.763 moles, 2.2 eq) and DBU (1,8-Diazabicyclo[5.4.0] undec-7-ene) (10.5g, 0.069 moles, 0.2 eq) at room temperature and stirred the reaction mass. 1-naphthol was added in single lot and heated to 70°C. The reaction was allowed to run at 70°C for 4-6 hours. After the completion of reaction, mixture was distilled and degassed. To the reaction, charged 50% solution of sodium hydroxide (13.88g, 0.347 moles, 1.0 eq) at room temperature and stirred for 1 hour. After the completion of reaction, charged dichloromethane (500 ml) and DM water (500ml) and stirred. The organic layers was separated and water layer is extracted with dichloromethane (100ml). Organic layer was again washed with DM water (100 ml) followed by brine solution (100ml). Organic layer was distilled and degased to obtain the compound of Formula IV as oily mass.
Example-3: Synthesis of propranolol free base of Formula VI
To a three neck round bottom flask was added, compound of Formula IV (65.3 g, 0.326 moles, 1.0 eq.) and cooled to 15°C, followed by addition of isopropyl amine 82.6g (70% aq. solution). The reaction was stirred at 55-60°C for 12-15 hours and monitored by HPLC. After completion of reaction, excess isopropylamine was recovered at 80°C under vacuum at 400-500 mbar. The crude mass thus obtained was dissolved in 260 ml of toluene. DM water (260 ml) was charged to the above clear solution and stirred for 15 min to separate layer. Water layer extracted with 50 ml toluene. Total toluene layer was washed with DM water (195 ml><2 times). Toluene layer was chilled to 5-10°C and stirred for 1.0 hr at 5-10 °C. The crude was filtered and washed with 65 ml of chilled toluene to obtain propranolol free base of Formula VI as off white solid material (61g, 72.2% yield, -98 % purity on HPLC).
Example-4: Synthesis of Propranolol hydrochloride of Formula I
To a stirred solution of propranolol free base of Formula VI (35.5g, 0.12 moles) in acetone (285 ml, 8V) was charged 1.775g (5%) activated carbon (pH= 5-7) and stirred for about 0.5 hours at 20-25°C. The resultant mixture was filtered through hyflo bed and washed with 70 ml acetone. The filtrate was charged in another three neck round bottom flask and pH was adjusted to 2.0 with cone. HC1 solution at 20-
n.g i NT 1 7 ~_IB^2i3-l-S—UZLLQbZ
16

25°C. The reaction mass was stirred for 10-12 hours, at 20-25°C for complete salt formation. The solid was filtered and washed with 70 ml acetone. Dried in hot air. oven at 45-50°C for 5-6 hours to obtain propranolol hydrochloride of Formula I (28.5g, 70.4% yield, and 99.5% purity).
ExampIe-5: One-pot synthesis of Propranolol free base of Formula VI
To a 1.0 L, three-necked round bottom flask fitted with condenser and temperature probe on a mechanical stirrer was charged epichlorohydrin (70.65g, 0.763 moles, 2.2eq), 1-naphthol (50.Og, 0.347 moles, 1.0 eq) and catalytic amount of N,N-diisopropylethylamine (8.97 g, 0.069 moles, 0.2 eq). The resultant mixture was heated to 110-115°C and was allowed to stir at same temperature for 2-3 hours. After completion of the reaction, as monitored by HPLC, the mixture was distilled under vacuum at 90°C to recover epichlorohydrin. The mixture was then cooled to 25-30°C. 50% aq. NaOH solution (13.88g, 0.347 moles, 1.0 eq) was added to the above thick oily reaction mass and stirred the reaction mass for about 5-6 hours at 20-25°C for complete conversion of l-chloro-3-(l-naphthoxy)-2-propanol of Formula V to (2-[(l-naphthyloxy)methyl]oxirane) of Formula IV. The reaction mass was then cooled to 10-15°C and charged isopropyl amine (61.57g, 1.04 moles, 3.0 eq.) under stirring and reaction was monitored at 55-60°C for 12-15 hrs. After completion of reaction as monitored by HPLC, unreacted isopropyl amine distilled at 80°C and toluene (250ml) was then added to the above obtained crude and heated to clear at 50°C. DM water (500ml) was charged to the above suspension arid stirred for 15 min to separate the layer. Water layer was extracted with 50 ml toluene. Total toluene layer was washed with 500 ml x 2 times, DM water. Toluene layer was charged in a 1 litre RBF and treated with 5% (2.5g) activated carbon for 0.5 hours. Above mixture was filtered through hyflo bed and washed with 200 ml toluene. The resultant pale yellow toluene was cooled under stirring tol0-15°C and solid mass thus obtained was stirred for 1.0 hours. The crude was filtered and washed with 50 ml chilled toluene to get Propranolol freebase of Formula VI (51 g dry, 56.70% yield, -98% on HPLC).


Example-6: Synthesis of propranolol hydrochloride of Formula I
To a stirred solution of propranolol free base of Formula VI (35.5g, 0.12 moles) in acetone (285 ml, 8V) was charged 1.775g (5%) activated carbon (pH= 5-7) and stirred for about 0.5 hours. The resultant mixture was filtered through hyflo bed and washed with 70 ml acetone. The filtrate charged in another three neck round bottom flask and pH was adjusted to 2.0 with cone. HC1 solution at 20-25°C. The reaction mass v^as stirred for 10-12 hours at 20-25°C for complete salt formation. The solid was filtered and washed with 70 ml acetone. Dried in hot air oven at 45-50°C for 5-6 hours to obtain propranolol hydrochloride of Formula I (27.3g, 67.4% yield, with 99% purity).

WE CLAIMS

An improved process for the preparation of propranolol hydrochloride of Formula I,


^

Formula I
wherein said process comprising the steps of:
a) refluxing 1-naphthol compound of Formula II with epichlorohydrin compound of Formula III in the presence of N?N-diisopropylethylamine (DIPEA) to obtain a reaction mixture comprising the compounds of Formula IV and Formula V


O
.+
DIPEA
CL CI
Formula II
Formula V
Formula IV
Formula III

b) treating.the reaction mixture of step a) with aq. sodium hydroxide to get the compound of Formula IV

Q ^O
Aq. NaOH

Formula V
Formula IV
Formula IV.

c) treating the compound of Formula IV with isopropyl amine to obtain propranolol free base of Formula VI 0
Formula VI
Formula IV
NH.


d) treating the propranolol free base of Formula VI with acetone and aq. hydrochloric acid;



Acetone Aq. HCI

Formula VI

Formula I

; and

e) isolating the propranolol hydrochloride of Formula I.
2. A one-pot process for preparation of propranolol free base of Formula VI,

Formula VI
wherein said process comprising of:
a) refluxing 1-naphthol of Formula II with epichlorohydrin of Formula III in presence of N,N-diisopropylethylamine for 2-3 hours at 110-115°C and obtaining a reaction mixture comprising the compounds of Formula IV and Formula V;
b) adding 50% aq. sodium hydroxide solution to the reaction mixture of step a) at room temperature for 5-6 hours and producing a reaction mixture comprising (2-[(l-naphthyloxy)methyl]oxirane) of Formula IV;
c) adding isoprbpyl amine to the to the reaction mixture of step b) at 10-15°C followed by stirring at 55-60°C for 12-15 hours;
d) extracting the reaction mixture of step c) with organic solvent and water; and
e) isolating the propranolol free base of Formula VI.
3. The process as claimed in claim 2, wherein said organic solvent used in step d) is selected from toluene, dichloromethane and ethyl acetate.

Formula A Formula B
4. The process as claimed in claim 1, wherein said propranolol hydrochloride of Formula I is substantially free of impurities of Formula A, B, C and D wherein each impurity is less than about 0.15% w/w,


Formula C Formula D
5. The process as claimed in claim 1, wherein propranolol hydrochloride of Formula I is characterized by X-ray powder diffraction (XRD) pattern having peaks at about 12.41, 12.77, 16.66, 17.15, 19.42, 19.83, 21.16, 22.00, 22.19, 24.99, and 26.98 ±0.2±0.2°29.
6. The process as claimed in claim 1, wherein propranolol hydrochloride of Formula I is'characterized by DSC with endotherm peak at 164.98°C.
7. The process as claimed in claim 1, wherein propranolol hydrochloride of Formula I is crystalline in nature and characterized by atleast one of:

a) an X-ray powder diffraction (XRD) pattern having peaks at about 12.41, 12.77, 16.66, 17.15, 19.42, 19.83, 21.16, 22.00, 22.19, 24.99, 26.98 ±0.2±0.2°20,
b) an X-ray powder diffraction (XRD) pattern as depicted in Fig. 1, or
c) DSC with endotherms peak at 164.98°C.

8. A composition comprising propranolol hydrochloride of Formula I prepared
. as per the process claimed in claim 1, wherein said composition further
comprises of atleast one pharmaceutical acceptable excipients thereof.
9. A composition comprising propranolol hydrochloride of Formula I,

Formula I
wherein said propranolol hydrochloride of Formula I is prepared by: a) refluxing 1-naphthol compound of Formula II with epichlorohydrin compound of Formula III in the presence of N,N-diisopropylethylamine (DIPEA) to obtain a reaction mixture comprising the compounds of Formula
IV and Formula V


DIPEA
0

Formula II

Formula HI

Formula IV

Formula V

b) treating the reaction mixture of step a) with aq. sodium hydroxide to get the compound of Formula IV

O *r-o
Aq. NaOH

Formula IV

Formula V

Formula TV.

c) treating the compound of Formula IV with isopropyl amine to obtain propranolol free base of Formula VI



NH-


Formula IV Formula VI
5
d) treating the propranolol free base of Formula VI with acetone and hydrochloric acid;



Acetone Aq. HCI

' Formula VI

Formula I

; and

e) isolating the propranolol hydrochloride of Formula I.