Synthesis of 3F-HGA

7/30/2019 Synthesis of 3F-HGA

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3-Fluoro-2,5-dihydroxyphenylaceticacid (18)

OMe B B r OH*COOH CH 2C1 2 ^-78 C-0 C

5 0 %17 18

In an oven-dried 250 ml round-bottomed flask with a magnetic stirring bar wasplaced 0.60 g (2.80 mm ol, 1.0 equiv) of 3-fluoro-2,5-dimethoxyp henylacetic acid (17) in25 ml of anhydrous CH2CI2. Then the reaction mixture was cooled down to -78 C and 8.5ml (9.24 m mol, 3.3 eq uiv) of 1M BBr3 in CH2CI2 was a dded d ropwise under nitrogenatmosph re. After 1 hour the tempratu re of the reaction was increase d to 0 C and thereaction mixture was stirred at 0 C for 3 hours. After that 10 ml of the cold water wasadded, the organic layer was removed from the water one. The organic layer was washedwith water (5x5 ml). The water fractions were combined, extracted with EtOAc (5x6 ml),then EtOAc-layer was dried over MgSO 4 and evaporated under reduced pressure. Theobtained light yellow oil was subjected to column chromatography. The product was elutedwith hexane/EtOA c (1/2) mixture to give 0.26 g of 3-fluoro-2,5-dihydroxyphenylaceticacid (18) as ros powder.Yield 50%M.p . 153 CR f 0.87 (hexane/EtOAc 1/1)'H NMR (400 MHz, acetone-J6) (ppm) 3.62 (s, 2H), 6.54 (dd, 1H, 3J H 4 ,F 9.6 Hz, 4JH4,H62.8 Hz), 6.51 (d, 1H, J 2.8 Hz)13C NM R (100 MH z, CD3OD) 8 (ppm) 36.4 (d, 5JC.F 12 Hz, C H 2), 103.2 (d, 2JC.F 88 Hz,C-4), 113.8 (d, 3JC -F 12 Hz , C-6), 126.4 (d, 3JC-F 16 Hz, C-l), 137.1 (d, 2JC-F60 Hz, C-2),151.2 (d, 3 J C - F 4 2 . 8 H Z , C-5), 153.4 (d, ' j C - F 943.2 Hz, C-3), 175.7IR (KBr, cm"1) 3408, 1725, 1694, 1505, 1353, 1254, 1137, 791The data of ]H spectrum were in accord with those reported in the literature. 37

Summary


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lactone which still forms during the reaction. Indeed, the carboxylic acid dissolves in waterwhereas the formed lactone stays in dichloromethane layer. Then the purification ofproduct on a silica gel column provided 6-chloro-2,5-dihydroxyphenylacetic acid (9) in50% yield.There are several causes to explain this moderate yield. The first is the lactoneformation during the reaction. The second is the partial dcomp osition of the product (9) onthe silica gel column when in use of purification. This is very polar compound whichmakes difficult the fast purification.

Thus, the synthesis of 6-chloro-2,5-dihydroxyphenylacetic acid (6-C1 HG A) (9) hasbeen accomplished in 8 steps and 12.5% overall yield.

4.3 Synthesis of 3-fluoro-2,5-dihydroxyph enylacetic acid (3-F HG A)We hve chosen 2-fluoro-4-methoxyphenol (12) as a started material. This

compound already contains the fluorine atom in the dsirable position of benzne ring.Subsquent slective ortho-hydroxymethylation of (12) allows synthesizing an intermediate(13) which contains in benzne ring the same substituents as that the final compound. Thefollowing modification of the side chain of (13) leads to 3-fluoro-2,5-dihydroxyphenylacetic acid (18) (Scheme 16).


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Scheme 1647

OMe

Et2AlCl ,(H 2CO )n20 C, 24 h8 1 %

COOH

OMe

OMe30%NaOH,MeOH60 C, 15 h72%

CH 3I, K 2CO 3,Actone 40 C, 15 h8 6 %

0C-20C3 h83%

PBr3,CH 2C1 2

OMe

BBr3,CH 2C1 2 -78 C-0 C4 h5 0 %

COOH

183-F HG A


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The first step of this synthesis is a very interesting. It is a questing of ortho-specifichydroxy alkylation of 2-fluoro-4-methoxypheno l (12). We hve tried to synthesize the3-fiuoro-2-hydroxy-5-methoxybenzyl alcohol (13) using several metho ds.

Firstly we used the reaction of paraformaldehyde with a mixture of phnol andexcess of boric acid in xylene. This method was developed by Yang 46 and allows yieldingo-hydroxybenzyl alcohols in a good yield. However, this method requires a lot ofman ipulations and drastic conditions. The first step of this reaction is formation of boroxinewhich takes place by heating of the corresponding phnol and boric acid at 180 C for 24hours under conditions of continuous azeotropic distillation of water. After thatparaformaldehyde is added to the reaction mixture and the reaction occurs at 80 C for 24hours. Unfortunately, following this protocol we hve not reached dsirable productbecause of dcomposition of the starting material.

The second route which we hve followed to synthesize the 3-fluoro-2-hydroxy-5-methoxybenzyl alcohol (13) required use of the paraformaldehyde in the prsence ofdiethylaluminium chloride47 (Scheme 17).

Scheme 17

E t2AlCl ,(H 2C O ) n F20 C, 24 h8 1 %

This reaction proceeds smoothly at 20 C for 24 hours by undergoing of 2-fluoro-4-methoxyphenol (12) with 5.0 quivalents of paraformaldehyde and 1.5 quivalents of 1ME2A1C1 in dichlorome thane. The yield of 3-fluoro-2-hydroxy-5-methoxybenzylalcohol (13) is 8 1 % after purification by column chromatography .

This method has been developed by Sartori48 group which is the gnerai tactic forC-ortho regiospecific laboration of variety of aromatic molcules via the electrophilic


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4')

aromatic substitution. The reaction key lies in the intermediacy of a quite rigid chelatetransition state (Scheme 18) in which the aluminum plays the rle of Lewis acid promoterand serves two functions: activation of the carbonyl carbon by coordination andregiocontrol of the process by keeping the reacting sites of the two reactants, i.e. carbonylcarbon atom of formaldehyde and ortho-carbon of phnol, into proximity.

Scheme 18

EU ..Et

OMe OMe OMe OMe

The next step of the synthesis is the slective protection of phenolic OH in theprsence of primary hydroxyl group in 3-fluoro- 2-hydroxy-5-methoxybenzyl alcohol (13)(Scheme 19):

OHi

OMe13

Scheme 19

C H 3I , K 2C O 3 ,\ n | . Actone40 C, 15 h

8 6 %1

OMe1

OMe14

3-Fluoro-2-hydroxy-5-methoxybenzyl alcohol (13) was placed with 2.0 quivalentsof K2CO3 and 4.0 quivalents of CH3I in actone. The reaction mixture was warmed to40 C for 15 hou rs. After that the inorganic layer w as filtered and the produet was subjeeted


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to column chromatography to yield 3-fluoro-2,5-dimethoxybenzyl alcohol (14) in excellentyield (86%).

The next step of the synthesis is the transformation of 3-fluoro-2,5-dimethoxybenzyl alcohol (14) into the corresponding alkyl bromide (15) (Scheme 20).

Scheme 20

OMe OMePB r3! CH 2C1 2: 0 C-20 C3 h86%

To a cooled (0 C) solution of 3-fluoro-2,5 dimethoxybenzyl alcohol (14) indichloromethane was added dropw ise 1.5 qu ivalen ts of 1M PBr3 in CH2CI2. After 3 hoursof reaction at 20 C the solvent was evaporated and the product of the reaction was purifiedby column chromatography to get bromom ethyl-3-fluoro-2,5-dimethoxybenzen e (15) in86% yield.

The two next steps include the incorporation of one more carbon in the side chain ofthe methylbrom ide-3-fluoro-2,5-dimethoxyb enzene (15) and subsquent hydrolysis ofobtained 3-fluoro-2,5-dimethoxypheny lacetonitrile (16) (Scheme 21).


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Scheme 21

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OM e OM eB r NaCN,DMSO F

20 C, 5 h100%

30% NaOH,MeOH !60 C, 15 h72%

OM eCOOH

The 3-fluoro-2,5-dimethoxyphenylacetonitrile (16) was obtained by undergoing ofbromom ethy-3-fluoro-2,5-dimethoxyben zene (15) with 2.0 quivalents of sodium cyanidein dimethylsulfoxide. This reaction smoothly proceeds under mildly conditions, (20 C, 5hours) with 100% yield.

To obtain 3-fluoro-2,5-dimethoxyphenylacetic acid (17), the 3-fluoro-2,5-dimethoxyphenylacetonitrile (16) was hydrolyzed under basic conditions using 30%aqueous solution of sodium hydroxide. We hve again used the basic condition to avoid thelactone formation. The reaction lasted 15 hours at 60 C with 72 % yield of the product afterchromatography.

The final step of the synthesis of 3-F HGA is the deprotection of two phenolicgroups. For this we hve followed the same protocol (Scheme 22) which we hve used inthe previous synthesis of 6-C1 HG A.

Scheme 22

OM e BBr3,COOH CH 2C1 2 ^-78 C-0 C4 h5 0 %

COOH


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To 3-fluoro-2,5-dimethoxyphenylacetic acid (17) was added dropw ise 3.3quivalents of 1M BBr3 in dichloromethane at -78 C. After one hour the temprature wasincreased to 0 C and after three hours the reaction was quenched with 5 ml of cold water.This time we hve not managed to separate the forming lactone from the final product bywashing the water layer with dichloromethane. The purification of product on a silica gelcolumn has allowed yielding 3-fluoro-2,5-dihydroxyphenylacetic acid (18) in 50% yield.

Thus, the synthesis of 3-fluoro-2,5-dihydroxyphenylacetic acid (3-F HGA) (18) hasbeen accomplished in 6 steps with 21.3% of overall yield.

Synthesis of 3F-HGA

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