CA1044255A - Process for preparing indene acetic acids - Google Patents
Process for preparing indene acetic acidsInfo
- Publication number
- CA1044255A CA1044255A CA215,636A CA215636A CA1044255A CA 1044255 A CA1044255 A CA 1044255A CA 215636 A CA215636 A CA 215636A CA 1044255 A CA1044255 A CA 1044255A
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- fluoro
- indene
- compound
- acetic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
- C07C45/66—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups by dehydration
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
- C07C45/75—Reactions with formaldehyde
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
- C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
- C07C49/807—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen all halogen atoms bound to the ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5456—Arylalkanephosphonium compounds
Abstract
ABSTRACT OF THE DISCLOSURE
Process for preparing 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indene-3-acetic acid by reacting fluorobenzene with an acid halide, to form an indanone, reaction of the indanone with a methylthio (or methylsul-finyl)benzyl compound to form 5-fluoro-2-methyl-1-(p-methylthiobenzyl) or (p-methylsulfinylbenzyl)-indene and reacting said indene with a glyoxylic acid. The invention also relates to intermediates thereof and processes for said intermediates.
Process for preparing 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indene-3-acetic acid by reacting fluorobenzene with an acid halide, to form an indanone, reaction of the indanone with a methylthio (or methylsul-finyl)benzyl compound to form 5-fluoro-2-methyl-1-(p-methylthiobenzyl) or (p-methylsulfinylbenzyl)-indene and reacting said indene with a glyoxylic acid. The invention also relates to intermediates thereof and processes for said intermediates.
Description
1,Y ?I~L125 5;
BACKGROUND OF THE INVENTION
The indene-3-acetic acid is a known compound having anti-lnflammatory activity as described in U.S.
Patent No. 3,654,349. The compound has been prepared by a number of methods as disclosed in the above-mentioned :
~ patent as well as Greek Patent No. 41,736. In one of the ., i methods described in the Greek patent, 5-fluoro-2-methyl-l-(p-methylsulfinylbenzyl)-indene is disclosed as an intermediate. This intermediate is reacted with a glycolic acid ester and the product is subsequently oxidized to the `~ ester of 5-fluoro-2-methyl-1-(p-methylsulfinylbenzyl)-~ indenylidene-3-acetic acid which is then isomerized and i, hydrolyzed to achieve the desired compound. Similarly in the Greek patent, the preparation of the indanone inter-mediate of this invention is described for the preparation of the indene starting material therein. The preparation 1 of said indanone, however, is quite different From the present preparation and involves reacting 3-nitrobenzalde-hyde with propionic anhydride to form the appropriate nitro-,~
cinnamic acid, reducing said compound to the corresponding amino compound and further reaction to form the ~-methyl- -;
l . . .
i . .
; : - , , :
. .~ , .
-I ', . . ., ~
';~
~ ~ ' . , .. , 1 .
s~ o~
':
1 3-fluorohydroci.nnc~mic acid. This compoun~, in -turn, is
BACKGROUND OF THE INVENTION
The indene-3-acetic acid is a known compound having anti-lnflammatory activity as described in U.S.
Patent No. 3,654,349. The compound has been prepared by a number of methods as disclosed in the above-mentioned :
~ patent as well as Greek Patent No. 41,736. In one of the ., i methods described in the Greek patent, 5-fluoro-2-methyl-l-(p-methylsulfinylbenzyl)-indene is disclosed as an intermediate. This intermediate is reacted with a glycolic acid ester and the product is subsequently oxidized to the `~ ester of 5-fluoro-2-methyl-1-(p-methylsulfinylbenzyl)-~ indenylidene-3-acetic acid which is then isomerized and i, hydrolyzed to achieve the desired compound. Similarly in the Greek patent, the preparation of the indanone inter-mediate of this invention is described for the preparation of the indene starting material therein. The preparation 1 of said indanone, however, is quite different From the present preparation and involves reacting 3-nitrobenzalde-hyde with propionic anhydride to form the appropriate nitro-,~
cinnamic acid, reducing said compound to the corresponding amino compound and further reaction to form the ~-methyl- -;
l . . .
i . .
; : - , , :
. .~ , .
-I ', . . ., ~
';~
~ ~ ' . , .. , 1 .
s~ o~
':
1 3-fluorohydroci.nnc~mic acid. This compoun~, in -turn, is
2 cyclized to form the indanone.
3 It is an object of this invention to provide new
4 px w esses for preparing 5-fluoro-2-methyl-1-(p-methylsul-finylbenzylidene)-indene-3-acetic acid. It is a further 6 object to prepare this compound via new processes which 7 are advantageous over the process described above. It is 8 still a further object to prepare the intermediat0 indanone 9 in a much shorter path, with higher yields than previously described.
; , :;~ 11 DETAILS OF T~E INVENTION
12 In accordance with one aspect of this invention, 13 it has been found that the subjec-t compound can be readily 14 prepared by a combination of reaction steps; namely, by .:: .
~ 15 reacting 5-fluoro-2-methyl-1-(p-methylthiobenz~ indene . .,i 16 with glyoxylic acid, its ester, ~alt or other derivative ~;` 17 which can form the free acid or salt under the reaction con-18 ditions of the process to form 5-fluoro-2-methyl-1-(p-~j 19 methylthiobenzyl)-indenylidene-3-acetic acid, ester or salt `~ ~ 20 which compound is then isomerized and subsequently oxidized , :1 21 to yield the desired product. (Steps 4, 6 and 7 of Flow i :;~',5,~ 22 Sheet I). Al~ernatively, the indenylidene-3-acetic acid -~
~ ~ 23 compound may be first oxidized and then isomerized. In :~ ~
24 another aspect o~ this invention, 5-fluoro-2-methyl-1-(p-~ 25 methylsulfinylbenzyl)-indene is reacted with glyoxylic acid, : ~
~ 26 its ester or salt to form directly 5-fluoro-2-methyl-1--:, ~1~ 27 (p-methylsulfinylbenzyl)-indenylidene-3-acetic acid, which !
~;~, 28 compound is subsequently isomerized to the desired product.
;~; 29 ~Steps 4 and 5 of Flow Sheet I). The 5-fluoro-2-methyl-1-'j~ 30 (p-methylsulfinyl~or methylthiotbenzyl)-indenylidene-3-~j 31 acetic acids are novel compounds and make up another aspect : ., ~ 32 of this invention. These compounds are useful as inter-:', .
.:~ - 2 -.
1 mediates for the preparation of 5-fluoro~2-~ethyl-1-(p-2 methylsulfinylbenz~lidene)-indene-3-acetic acid, as well 3 as final products, as it has been foun~ that they similar-4 ly possess anti-inflammatory activity and could be useful
; , :;~ 11 DETAILS OF T~E INVENTION
12 In accordance with one aspect of this invention, 13 it has been found that the subjec-t compound can be readily 14 prepared by a combination of reaction steps; namely, by .:: .
~ 15 reacting 5-fluoro-2-methyl-1-(p-methylthiobenz~ indene . .,i 16 with glyoxylic acid, its ester, ~alt or other derivative ~;` 17 which can form the free acid or salt under the reaction con-18 ditions of the process to form 5-fluoro-2-methyl-1-(p-~j 19 methylthiobenzyl)-indenylidene-3-acetic acid, ester or salt `~ ~ 20 which compound is then isomerized and subsequently oxidized , :1 21 to yield the desired product. (Steps 4, 6 and 7 of Flow i :;~',5,~ 22 Sheet I). Al~ernatively, the indenylidene-3-acetic acid -~
~ ~ 23 compound may be first oxidized and then isomerized. In :~ ~
24 another aspect o~ this invention, 5-fluoro-2-methyl-1-(p-~ 25 methylsulfinylbenzyl)-indene is reacted with glyoxylic acid, : ~
~ 26 its ester or salt to form directly 5-fluoro-2-methyl-1--:, ~1~ 27 (p-methylsulfinylbenzyl)-indenylidene-3-acetic acid, which !
~;~, 28 compound is subsequently isomerized to the desired product.
;~; 29 ~Steps 4 and 5 of Flow Sheet I). The 5-fluoro-2-methyl-1-'j~ 30 (p-methylsulfinyl~or methylthiotbenzyl)-indenylidene-3-~j 31 acetic acids are novel compounds and make up another aspect : ., ~ 32 of this invention. These compounds are useful as inter-:', .
.:~ - 2 -.
1 mediates for the preparation of 5-fluoro~2-~ethyl-1-(p-2 methylsulfinylbenz~lidene)-indene-3-acetic acid, as well 3 as final products, as it has been foun~ that they similar-4 ly possess anti-inflammatory activity and could be useful
5 for the same purpose as descxibed for the final produ~t
6 of this process.
7 In still another aspe~t of this invention, the
8 5-fluoro-2-methyl-1-(p-methylthiobenzyl or ~p-methylsul-
9 finylbenzyl~)-indene is prepared by reaction of 5-fluoro
10 2-methyl-1-indanone with a p-methylthiobenzyl or p-~r 11 methyl~ulfinyl compound under Grignard or Wittig conditions i 12 to form 5-fluoro-2-methyl-1-(p-methylthio~or p-methylsulfinylt A 13 benzyl)-indene, which in turn is furtner reacted as described ~ 14 above. (Steps 3 to 5 or 3, 4, 6, and 7 of Flow Sheet I.) :
In a ~till further aspect of this invention, the 16 5-fluoro-2-methyl-1-indanone is prepared by reaction of an 17 appropriate ketone under Friedel Crafts conditions to form ;~
18 the desired 5-fluoro-2-methyl-1-indanone which is further 19 reacted as described above. (Steps 2 to 5 or 2 to 4, 6 and 7 of Flow Sheet I.) 21 Finally in still another aspect of this invention, 22 the ketone is prepared by reaction of fluorobenzene with 23 an appropriate~acid halide under Friedel Crafts conditions 24 to form the desired ketone and further reacted as described above. (Steps 1 to 5 or 1 to 4, ~ and 7 of Formula I.) . .,~
~ 26 In this step, the Friedel Crafts reaction may be allowed .. ~ ~ `
27 to continue such that the intermediate ketone formed is 28 cyclized in situ to the 5-fluoro-2-methyl indanone.
29 The invention and its sevexal aspects may be i~ 30 ~urther described by the following Flow Sheet.
... .
...
., .. , ,:.1 .t .
. ~. . . .
... . .. . .. . . .. . .
FLOW SHEET I
F~ + G-C-C-Z -- ~ ~ A
B (~ ) ~C-C-G
B
.`.~ I .
~/JC 3 C~ H3 ~
` 1 2 ,~
~1 ~ F~2 COOH
P~300~/~/ 0~33 CH2 J~
~ ~H~Coo~
3~ Rl H ~ :
3 CEI9 o~ 0~ ~3-CE:3 ~; ~ S-CH3 ~j :
: ~
~, ~ ,, - . . . . - . ~ .
, 1 ~ore sp2cifically, the condensation reaction 2 between the 5-fluoro-2-methyl~l-(p-methylthio~or methylsul-3 finyltben~yl)-indene and glyoxylic acid is carried out in 4 the presence of a strong base. Accordingly, bases such as alkali and alkali earth hydroxides tNaOH, KOH) especially 6 in the presence of a quaternary ammonium halide as catalyst 7 (such as Cl 6 trialkylbenzyl ammonium halide or tetra Cl 6 ~: 8 alkyl ammonium halide, i.e., 0.1 to 1.0 mole halide ~o :.
9 hydroxide), alkali or alkali earth Cl 5 alkoxide (NaOCH3, K-tertbutoxide), tetra Cl 6 alkyl ammonium hydroxide or ben-
In a ~till further aspect of this invention, the 16 5-fluoro-2-methyl-1-indanone is prepared by reaction of an 17 appropriate ketone under Friedel Crafts conditions to form ;~
18 the desired 5-fluoro-2-methyl-1-indanone which is further 19 reacted as described above. (Steps 2 to 5 or 2 to 4, 6 and 7 of Flow Sheet I.) 21 Finally in still another aspect of this invention, 22 the ketone is prepared by reaction of fluorobenzene with 23 an appropriate~acid halide under Friedel Crafts conditions 24 to form the desired ketone and further reacted as described above. (Steps 1 to 5 or 1 to 4, ~ and 7 of Formula I.) . .,~
~ 26 In this step, the Friedel Crafts reaction may be allowed .. ~ ~ `
27 to continue such that the intermediate ketone formed is 28 cyclized in situ to the 5-fluoro-2-methyl indanone.
29 The invention and its sevexal aspects may be i~ 30 ~urther described by the following Flow Sheet.
... .
...
., .. , ,:.1 .t .
. ~. . . .
... . .. . .. . . .. . .
FLOW SHEET I
F~ + G-C-C-Z -- ~ ~ A
B (~ ) ~C-C-G
B
.`.~ I .
~/JC 3 C~ H3 ~
` 1 2 ,~
~1 ~ F~2 COOH
P~300~/~/ 0~33 CH2 J~
~ ~H~Coo~
3~ Rl H ~ :
3 CEI9 o~ 0~ ~3-CE:3 ~; ~ S-CH3 ~j :
: ~
~, ~ ,, - . . . . - . ~ .
, 1 ~ore sp2cifically, the condensation reaction 2 between the 5-fluoro-2-methyl~l-(p-methylthio~or methylsul-3 finyltben~yl)-indene and glyoxylic acid is carried out in 4 the presence of a strong base. Accordingly, bases such as alkali and alkali earth hydroxides tNaOH, KOH) especially 6 in the presence of a quaternary ammonium halide as catalyst 7 (such as Cl 6 trialkylbenzyl ammonium halide or tetra Cl 6 ~: 8 alkyl ammonium halide, i.e., 0.1 to 1.0 mole halide ~o :.
9 hydroxide), alkali or alkali earth Cl 5 alkoxide (NaOCH3, K-tertbutoxide), tetra Cl 6 alkyl ammonium hydroxide or ben-
11 zyl tri-Cl ~ alkyl ammonium hydroxide~ (benzyltrimethyl
12 ammonium hydroxide) ~Triton Bt may be used. Preferably, tri-
13 alkylbenYyl ammonium hydroxide or tetra-alkyl ammonium :~
14 hydroxide is used as the strong base. The reaction can be 3 15 carried out without a solvent, but preferably a solvent is , ~ .
~ 16 used which is either added to the reaction mixture or .!~ 17 employed in conjunction with the strong base. C1 5 alkanols .! 18 (methanol, butanol), aromatic solvents such as benzene, ~ 19 pyridine and toluene or dioxane, acetonitrile, dimethylformamide, , ~ .
triglyme, dimethylsulfoxide, water and mixtures of water and 21 organic solvents may be employed. In fact, any solvent in 22 which the indene and glyoxylic acid are sufficiently soluble , ~:
~ 23 can be employed. Preferably, the solvent is Cl 5 alkanol, ,~ 24 especially methanol. The mole ratio of base to glyoxylic ~;~ 25 acid should be at least slightly more than one mole to one, `-3 26 but preferably about 1.1 to abou~ 4.0 moles of base to :
- 27 glyoxylic acid and especially 1.2 to 2.5. The mole ratio 3 28 of glyoxylic acid to indene is not critical and may con-29 veniently be from about 1 to 3.0 moles to one and preferably i 30 about 1.5 to 1.0 moles of indene. Alternatively, one may : ~ :
31 use the alkali or alkali earth salt or aryl or alkyl ester~
;1 _ ~ _ ., . ::.j:: .
:: -.. .. . . .. . . ..
``` 1557 6IA
f-k~
1 especially Cl 5 alkyl, i.e., methyl, ethyl, butyl in place 2 of the glyoxylic free acid or any other acid salt of a 3 strong base, as the starting material. Under these circum-4 stances, the amount of strong base employed in the reaction with glyoxylic acid salt or ester need be no more than a 6 catalytic amount, although the ratio indicated above may 7 also be employed. The order of addition of the reactants . .
8 is not critical; however, it is preferred to add the 9 glyoxylic acid compound to the reaction mixture of indene and base. The time of reaction is not critical, the 11 reaction being carried out until substantial completion.
12 Preferably, however, the reaction is carried out from 15 ~1 .
~;~ 13 minutes to about 5 hours and especially from a~out 1/2 to 14 3 hours. The reaction may be carried out from about 0C to .~
about 150C, preferably from about 10C to 80~C and ~; 16 especially from 35C to 60C.
.j 17 After the condensation reaction is complete, 18 the isomerization of the thus formed 5-fluoro-2-methyl-1-19 (p-methylthio~or methylsulfinyl~benzyl)-indenylidene-3-acetic acid, in the form of its acid addition salt or , .
21 ester, may be carried out without isolation; that is, the 22 same reaction mixture from the glyoxylic acid reaction can .
:, ~ 23 be used for the isomerization. This is particularly true :!
24 when one desires to carry out the isomerization under basic 25 condition~, since the reaction mixture from the previous 26 step is already basic and merely continued reaction will t 27 lead to the isomerization product. On the other hand, one 28 may wish to use other strong basesi for the isomerization.
29 Such bases as those described for the previous reaction may be employed. Preferably, however, the isomerization is s ~ - 6 -: ' , ,'1 ~ ~ 15576IA
1 carried out with the use of acid, and accordingly the re-2 action prGduc~ ~xom the previous step is preferahly first 3 isol~ted. various organic and/or inorganic acids may be 4 employed such as Cl 5 alkylsulfonic acids (methanesulfonic), arylsulfonic acids (toluene sulfonic acid), acidic ion 6 exchange resins (i.e., Dowex~50), arylcarbo~ylic acids 7 (p-nitrobenzoic acid), aliphatic acids (alkanoic acids 8 such as ace~ic acid, prOpioniG acid, trichloroacetic acid 9 and trifluoroacetic acid), mineral acids (phosphoric acid, hydrochloric acid, hydrobromic acid and sulfuric acid), but 11 preferably mineral acids or mixtures of mineral acids and 12 organic acids (preferably C2 5 alkanoic acids) such as 13 hydrochloric and acetic acid, hydrobromic and propionic acid ~
14 are employed. ~he xatio of acid to indenylidene is not ~-critical and one may therefore suitably use catalytic 16 quantities of acid. All that is necessary is that the re- -~ I .
17 action mixture be made acid in the event that it may be 18 basic. It is preferred, however, to use about 0.1 to 50 ~3 i 19 moles of acid to indenylidene and especially 1.0 to 20.
`~ 20 The r~action may be carried out with our without a solvent, ~;1 21 and when solvents are employed those previously mentioned :.
22 for the glyoxylic acid reaction, which are inert, may be used, . .1 i, 23 as well as halogenated hydrocarbons such as aliphatic ,~ .
24 halides (ethylene dichloride) or halobenzenes. Preferably, the reaction is carried out with an acid or a halogenated 26 hydrocarbon as solvent. when a weak acid is employed as 27 solvent it is preferred to also employ a strong acid such 28 as the arylsulfonic acids or mineral acids. For 29 example, one could use the unsub.stituted alkanoic acids , . :1 :,,, . .^ .
~ 7 -:., . ~
~Z~
;~ 1 (i.e., ac~tic acid) as solv~nt and the arylsulfonic (toluene-2 sulfonic acid) and especlally mineral acids (i.e., hydro-3 chloric acid). When halogenated hydrocarbons are employed 4 as solvents, it is preferred to use mineral ~cids as cata lysts and especially a~ anhydrous mineral ~cid such as hydro-6 gen chlor~de. The time and temperature of ;I 7 reaction is not critical, the higher the temperatur~ the ~ shorter the reaction time needed to substantially complete ,~ the reaction. Accordingly, the reaction may be carried 10 out at a temperature of about 0C to about 150C and pre-11 ferably from about 50C to 110C. Similarly, the reaction 12 time is preferably at least 30 minutes and may be up to i 1~ one or more days. After completion of the isomerization 1~ reaction, the product may be isolated by standard techniques such as filtration, extraction or removal of the acid :, 1l5 solvent by evaporation.
17 When one uses the p-methylthio compound as the I 13~starting material, oxidation of the methylthio group to the .f 1~ desired methylsulfinyl group may ~e carried out at any 2~ stage of the reaction process such as immediately after 21 reaction with glyo~ylic acid or after isomerization, but ; 22 preferably after isomerization. The oxidation may be 23 carried out by any number of standard techniques such as ~3~ 24 oxidation with H2O2, basic periodates or hypohalites, pre-25 ferably the alkaline or alkaline earth periodates and 26 hypohalites or organic peracids such as peracetic acid and 2~ monoperphthalic acid. Preferably, however, the oxidiæing 2~ agent is H2O2. The reaction is preferably carried out in ~29 the presence ~f a solvent. For such purposes Cl_5 alkanoic acids (acetic acid), halogenated hydrocarbons (chloroform), 1 ethers (dioxane), Cl 5 alkanols ~isopropanol) or mixtures 32 thereof may be used.
,~, - 8 -::~
~, . . .
, l The mole ratio of oxidizing a~en~ to indene 2 compound may be from .5 to 10 but preferably from .8 to 1.5O
3 The reaction time and temperature are not critical~ the re-` 4 action being carried out until substantial completion. Pre-5 ferably, however, the time of reaction is from l to 18 hours 6 and especially 2 to 6 hours at a temperature of 10C to 80C
7 and especially 25C ~o 50C.
-j 8 In the event that one desires to use an ester o~
g glyoxylic acid, the final free acid compound is readily ~
lO obtained during the isomerization especially if some water ; ~ -Ll is present and when the isomerization is carried out at 12 elevated temperatures. The type of ester used is not . i .
.`.,,~j ~, 13 critical since it can be made to readily come of~ during the s 14 reaction. Accordingly aliphatic, aromatic or heterocyclic i 15 esters may be employed such as alkyl (methyl, t-butyl, ;i~ L6 phenyl, alkenyl) or aryl (benzyl, phenyl). Glyoxylic ~ 17 acid salts may also be used such as the pharmaceutica1ly S'J 18 acceptable salts as well as other~ which are converted to the .~
; l9 free acid by hydrolysis, such salts as alkali or alkali ~;j 20 earth (Na, K, Ca, Li) as well as salts of the metals pre- -21 viously described in the Friedel Crafts reaction.
. .
j 22 The 5-fluoro-2-methyl-l-(p-methylthio~or methyl-23 sulfinyl~benzyl)-indene may be pxepared from 5-fluoro-2-:
`, 24 methyl-l-indanone by reaction with a p-methylthio(or methyl- ~-`~ 25 suLfinyl~-benzyl compound under Grignard or Wi*tig type 26 conditions. This indene contains the double bond in the l 27 to 2 position. However, under certain conditions, in its 28 formation some of the tautomeric indene compounds are 2g present. When these isomers are reacted in the presence of ., ~ .
`il 30 a base as in the reaction with glyoxylic acid, the same 1 indenyl anion is formed which reacts with glyoxylic acid ~J ~
.,:.' g _ .~ -,.
: ~ ,.":.. "", : , r ~ 15576IA
f~?"~ f,~ S
, 1 in the same way, ~i~iny the ind~ne compound. For example, 2 the Grignard o~ p-methylth.iobenzyl chloride or the Wittig re-; 3 agent of p-methylsulfinylbenzyl triphenylphosphonium chloride 4 is reacted with 5--fluoro-2-methyl-1-indanone under Grignard or Wittig conditions, respectively. In the case of the 6 Grignard reaction, the benzyl indene compound is obtained 7 directly; whereas with the Wittig reaction, one obtains for 8 the most part the benzylidene in~ane compound. In this 9 latter case, the benzylidene is isomerized to the benzyl com-pound under acid conditions by well known means for isomeriza-11 tion.
12 More specifically, the benzyl group is attached to 13 the indanona compound via a ~rignaxd or Wittig reaction under 14 well known conditions~ For example, in the Grignard reaction to metallic magnesium in absolute ether is added the appro-: j .
~ 16 priate benzyl halide (Cl, Br, F, I) tp-methylthiobenzyl halide . ~. ,!
17 or p-methylsulfinylbenzyl halidet and the reaction mixture heated preferabl~ from 25 to 35C. Although more or less 19 than an equimolar amount o~ magnesium may be used, it is 3~ 20 ad~antageous to use 3-6 ~old excess relative to the benzyl 21 halide. Although diethylether is usually used as the sol-22 vent, other ethers may be similarly used such as di-n-butyl, 23 diisopentyl ethers, anisole, cyclic ethers such as tetra-~: :
24~ hydropyran, 4-methyl-1,3-dioxane, d;hydropyran, tetrahydro-~ 2~5 furfuryl methyl ether, ethyl ether, furan and 2-ethoxy-;~ ~-~ 26 tetrahydrofuran. Tertiary amines such as dimethylaniline, ; ~ 27 hydrocarbons such as benzene and toluene, as well as ~ 28 many other type solvents described in the literature , ~ ~ :
29 can be also used~ The Grignard reagent thus prepared may be suitably used as is for reaction with 31 the indanone. The indanone and Grignard are admixed j . -;`,'1 ji 1~S76 1 (preferably indanone to Grignard) at a temperature of from 2 about 0C to the boiling point of the solvent and prefer~bly 3 20 to 35C. The concentrations of reactants are not criti 4 cal; however ~or best results, about equimolar quantities of each are used. The complex thus formed is reacted as 6 is usually done with Grignard reactions with an acid. In-7 organic mineral acids such as HCl, H2SO4 and phosphoric 8 acids may be used as well as organic or aliphatic acids 9 such as acetic, propionic or methanesulfonic. Usually, at - 10 least a 5-10% molar excess of acid to complex is used. It .:
11 is preferred to add the acid to the complex reaction mixture 12 usually as a dilute solution in water, although other 13 solvents for the acid may also be used such as alcohols, 14 ethers or aromatic hydrocarbons. The reaction temperature is usually 0 to 100C, although 20 to 40C is preferred.
16 In the Wittig reac~ion, for example, triphenyl-17 phosphine or a substituted triphenylphosphine is reacted 18 with the appropriate benzyl halide (p-methylthio or p-:.
19 methylsulfinylbenzyl halide) in the melt or in the pre-sence of suitable solvents to form the intermediate phos-21 phonium salt. Such solvents as (aromatic) benzene, nitro-22 benzene, xylene (ethers) diethyl ether, acetonitrile or -23 dimethylformamida, (aliphatic) nitromethaner formic acid, 24 acetic aoid and ethylacetate as well as many others described in the literature may be used. The preparation 26 of the phosphonium salt is carried out under temperatures 27 well known to the art such as from 0 to 200C and especially 28 25 to 75C , at atmospheric pressure as well as under 2~ pressure. The molar concentration of the triphenylphos-phine to ~he benzyl halide may suitably vary from 2 moles 31 to 1 mole and preferably 1~2 moles to 1 mole. The phos-32 phonium salt is not necessarily isolated and is converted ,, ~ ~49~5 l to the Wittig reagen~ employing either the organometallic ; 2 or alkoxide method. In the former method, phenyl lithium 3 or n-butyl lithium is the usual proton acceptor and di-4 ethyl ether or tetrahydrofuran, the solvent. In the latter method an alkali metal alkoxide may be used as the 6 proton acceptor and corresponding alcohols as the solvent~
7 The Wittig reagent is usually not isolated but `I 8 rather is allowed to react in the same reaction ~essel.
9 The reaction of the bases with the phosphonium salt is suitably carried out on about an equimolar basis, although 11 an excess of base may be advantageously used. The re-12 action may be carried out at a temperature of from 0C to . .
13 the boiling point of the solvent and preferably from 25 to ` ~ 14 50C~ AEter addition of ~.he base, the indanone compound is then added, suitably about equimolar wi h the Wittig re-16 agent, although more or less may be usedO
~ 17 The reaction may be carrie~ out at temperatures of from ;i 18 0C to the boiling point of the solvent but preferably 25 ., 19 to 50C until the reaction is substantially complete. The indene intermediate may then be isolated by standard ' :jt 21 techniques. In those cases wherein the Wittig reagent is 22 -first isolated, the reaction with the indanone may be 23 readily carried out in a variety of inert solvents. Solvents 24 such as ether~ benzene, ethylacetate, hexane or petroleum ether may be suitably used.
26 The 5-fluoro-2-methyl-l-indanone is prepared 27 from a ketone of the formula:
C - C - G
O
) . -~ ~ - 12 -.. ; .. . - , . . . . . . .
` 15576IA
$
1 wherein A is methyl or toyether with G forms methylidene:
2 B is hydrogen, methyl or halo (Cl, Br, F, I); G is 3 methyl, CH2R or together with A forms methylidene, wherein .
4 R is halo (Cl, Br, F, I), hydroxy, its ethers or esters ~such as from alkanols ~especially Cl 5 alkanols), alkanoic 6 acids ~especiall~r C2 5 alkanoic acids), aromatic acids 7 ~especial~y C7 9 aromatic acids), mineral acids, i.e., 8 methanol, propanol, acetic acid, propionic acid, methane 9 sulfonic acid, p-toluenesulfonic acid, phosphoric acid, and the like) or -N-(Cl 5 alkyl)2 especially methyl and 11 ethyl; and when A and G together is methylidene, B is ~ 12 methyl; when A and G are each methyl, B is halo; and when .',.! 13 A is methyl and B is hydrogen, G is CH2R; is reacted under 14 Friedel Crafts conditions to form 5-fluoro-2-methyl-1--~ 15 indanone. Preferably, the ketone starting material is 16 2-bromo-4'-fluoro-2-methylpropiophenone (when A and G are 17 each methyl and B is halogen) but may suitably also be 4'-18 fluoro-2-methylacrylophenone, 3-chloro-4'-fluoro-2-methyl-l 19 propiophenone, 4'-fluoro-3-hydroxy-2-methylpropiophenone . ~l or 3-dimethylamino-4'-fluoro-2-methylpropiophenone. The 21 reaction is suitably carried out under normal Friedel Crafts '~ 22 conditions. For example, the ketone is reacted in the pre-`'3, 23 sence of such Friedel Crafts catalysts as Lewis acids, 24 metal~alkyls and alkoxides, Bronsted acids, acidic oxides and sulfides, cation exchange resins, metathetic cation 26 ~orming agents and stable carbon.ium and related complexes.
27 Lewis acids such as those of the acid halide type ~metal 28 halides), i.e., aluminum chloride or bromide, BeC12, CdC12, 29 ZnC12, BF3, BC13, BBr3, GaC13, ~aBr3, TiC14, TiBr4, ZrC14, i~ 30SnC14, SnBr4, SbC15, SbC13, BiC13, FeC13 and UC14 may .'; ~;
.,~,, ~' ~ ~ 13 Z~
1 be suitably used. Also, when the ketone is the a or ~-halo~
2 isobutyrophenone, the metals p~r se may be used as catalysts, 3 since in the couxse of the reaction the halo compound reacts 4 with the metal forming the corresponding metal halide, 5 which in turn assists in furthering the reaction. This 6 class of Friedel Crafts catalysts is preferred and parti-7 cularly the use of an aluminum or iron halide. The metal ~; 8 alkyl and alkoxides which can be suitably used are~ for 9 example, aluminum or boron alkyls (methyl, ethyl, propyl) 10 or alkoxides ~methoxide, ethoxide or propoxide3. Bronsted 11 acids which c~n be suitably used are, for example, sulfuric, -`s 12 phosphoric, polyphosphoric, perchloric, chlorosulfonic, ~ 13 fluorosulfonic, alkyl and arylsulfonic (ethane, p-toluene~
~1 9 14 and related aromatic sulfonic acids~ as well as chloroacetic i
~ 16 used which is either added to the reaction mixture or .!~ 17 employed in conjunction with the strong base. C1 5 alkanols .! 18 (methanol, butanol), aromatic solvents such as benzene, ~ 19 pyridine and toluene or dioxane, acetonitrile, dimethylformamide, , ~ .
triglyme, dimethylsulfoxide, water and mixtures of water and 21 organic solvents may be employed. In fact, any solvent in 22 which the indene and glyoxylic acid are sufficiently soluble , ~:
~ 23 can be employed. Preferably, the solvent is Cl 5 alkanol, ,~ 24 especially methanol. The mole ratio of base to glyoxylic ~;~ 25 acid should be at least slightly more than one mole to one, `-3 26 but preferably about 1.1 to abou~ 4.0 moles of base to :
- 27 glyoxylic acid and especially 1.2 to 2.5. The mole ratio 3 28 of glyoxylic acid to indene is not critical and may con-29 veniently be from about 1 to 3.0 moles to one and preferably i 30 about 1.5 to 1.0 moles of indene. Alternatively, one may : ~ :
31 use the alkali or alkali earth salt or aryl or alkyl ester~
;1 _ ~ _ ., . ::.j:: .
:: -.. .. . . .. . . ..
``` 1557 6IA
f-k~
1 especially Cl 5 alkyl, i.e., methyl, ethyl, butyl in place 2 of the glyoxylic free acid or any other acid salt of a 3 strong base, as the starting material. Under these circum-4 stances, the amount of strong base employed in the reaction with glyoxylic acid salt or ester need be no more than a 6 catalytic amount, although the ratio indicated above may 7 also be employed. The order of addition of the reactants . .
8 is not critical; however, it is preferred to add the 9 glyoxylic acid compound to the reaction mixture of indene and base. The time of reaction is not critical, the 11 reaction being carried out until substantial completion.
12 Preferably, however, the reaction is carried out from 15 ~1 .
~;~ 13 minutes to about 5 hours and especially from a~out 1/2 to 14 3 hours. The reaction may be carried out from about 0C to .~
about 150C, preferably from about 10C to 80~C and ~; 16 especially from 35C to 60C.
.j 17 After the condensation reaction is complete, 18 the isomerization of the thus formed 5-fluoro-2-methyl-1-19 (p-methylthio~or methylsulfinyl~benzyl)-indenylidene-3-acetic acid, in the form of its acid addition salt or , .
21 ester, may be carried out without isolation; that is, the 22 same reaction mixture from the glyoxylic acid reaction can .
:, ~ 23 be used for the isomerization. This is particularly true :!
24 when one desires to carry out the isomerization under basic 25 condition~, since the reaction mixture from the previous 26 step is already basic and merely continued reaction will t 27 lead to the isomerization product. On the other hand, one 28 may wish to use other strong basesi for the isomerization.
29 Such bases as those described for the previous reaction may be employed. Preferably, however, the isomerization is s ~ - 6 -: ' , ,'1 ~ ~ 15576IA
1 carried out with the use of acid, and accordingly the re-2 action prGduc~ ~xom the previous step is preferahly first 3 isol~ted. various organic and/or inorganic acids may be 4 employed such as Cl 5 alkylsulfonic acids (methanesulfonic), arylsulfonic acids (toluene sulfonic acid), acidic ion 6 exchange resins (i.e., Dowex~50), arylcarbo~ylic acids 7 (p-nitrobenzoic acid), aliphatic acids (alkanoic acids 8 such as ace~ic acid, prOpioniG acid, trichloroacetic acid 9 and trifluoroacetic acid), mineral acids (phosphoric acid, hydrochloric acid, hydrobromic acid and sulfuric acid), but 11 preferably mineral acids or mixtures of mineral acids and 12 organic acids (preferably C2 5 alkanoic acids) such as 13 hydrochloric and acetic acid, hydrobromic and propionic acid ~
14 are employed. ~he xatio of acid to indenylidene is not ~-critical and one may therefore suitably use catalytic 16 quantities of acid. All that is necessary is that the re- -~ I .
17 action mixture be made acid in the event that it may be 18 basic. It is preferred, however, to use about 0.1 to 50 ~3 i 19 moles of acid to indenylidene and especially 1.0 to 20.
`~ 20 The r~action may be carried out with our without a solvent, ~;1 21 and when solvents are employed those previously mentioned :.
22 for the glyoxylic acid reaction, which are inert, may be used, . .1 i, 23 as well as halogenated hydrocarbons such as aliphatic ,~ .
24 halides (ethylene dichloride) or halobenzenes. Preferably, the reaction is carried out with an acid or a halogenated 26 hydrocarbon as solvent. when a weak acid is employed as 27 solvent it is preferred to also employ a strong acid such 28 as the arylsulfonic acids or mineral acids. For 29 example, one could use the unsub.stituted alkanoic acids , . :1 :,,, . .^ .
~ 7 -:., . ~
~Z~
;~ 1 (i.e., ac~tic acid) as solv~nt and the arylsulfonic (toluene-2 sulfonic acid) and especlally mineral acids (i.e., hydro-3 chloric acid). When halogenated hydrocarbons are employed 4 as solvents, it is preferred to use mineral ~cids as cata lysts and especially a~ anhydrous mineral ~cid such as hydro-6 gen chlor~de. The time and temperature of ;I 7 reaction is not critical, the higher the temperatur~ the ~ shorter the reaction time needed to substantially complete ,~ the reaction. Accordingly, the reaction may be carried 10 out at a temperature of about 0C to about 150C and pre-11 ferably from about 50C to 110C. Similarly, the reaction 12 time is preferably at least 30 minutes and may be up to i 1~ one or more days. After completion of the isomerization 1~ reaction, the product may be isolated by standard techniques such as filtration, extraction or removal of the acid :, 1l5 solvent by evaporation.
17 When one uses the p-methylthio compound as the I 13~starting material, oxidation of the methylthio group to the .f 1~ desired methylsulfinyl group may ~e carried out at any 2~ stage of the reaction process such as immediately after 21 reaction with glyo~ylic acid or after isomerization, but ; 22 preferably after isomerization. The oxidation may be 23 carried out by any number of standard techniques such as ~3~ 24 oxidation with H2O2, basic periodates or hypohalites, pre-25 ferably the alkaline or alkaline earth periodates and 26 hypohalites or organic peracids such as peracetic acid and 2~ monoperphthalic acid. Preferably, however, the oxidiæing 2~ agent is H2O2. The reaction is preferably carried out in ~29 the presence ~f a solvent. For such purposes Cl_5 alkanoic acids (acetic acid), halogenated hydrocarbons (chloroform), 1 ethers (dioxane), Cl 5 alkanols ~isopropanol) or mixtures 32 thereof may be used.
,~, - 8 -::~
~, . . .
, l The mole ratio of oxidizing a~en~ to indene 2 compound may be from .5 to 10 but preferably from .8 to 1.5O
3 The reaction time and temperature are not critical~ the re-` 4 action being carried out until substantial completion. Pre-5 ferably, however, the time of reaction is from l to 18 hours 6 and especially 2 to 6 hours at a temperature of 10C to 80C
7 and especially 25C ~o 50C.
-j 8 In the event that one desires to use an ester o~
g glyoxylic acid, the final free acid compound is readily ~
lO obtained during the isomerization especially if some water ; ~ -Ll is present and when the isomerization is carried out at 12 elevated temperatures. The type of ester used is not . i .
.`.,,~j ~, 13 critical since it can be made to readily come of~ during the s 14 reaction. Accordingly aliphatic, aromatic or heterocyclic i 15 esters may be employed such as alkyl (methyl, t-butyl, ;i~ L6 phenyl, alkenyl) or aryl (benzyl, phenyl). Glyoxylic ~ 17 acid salts may also be used such as the pharmaceutica1ly S'J 18 acceptable salts as well as other~ which are converted to the .~
; l9 free acid by hydrolysis, such salts as alkali or alkali ~;j 20 earth (Na, K, Ca, Li) as well as salts of the metals pre- -21 viously described in the Friedel Crafts reaction.
. .
j 22 The 5-fluoro-2-methyl-l-(p-methylthio~or methyl-23 sulfinyl~benzyl)-indene may be pxepared from 5-fluoro-2-:
`, 24 methyl-l-indanone by reaction with a p-methylthio(or methyl- ~-`~ 25 suLfinyl~-benzyl compound under Grignard or Wi*tig type 26 conditions. This indene contains the double bond in the l 27 to 2 position. However, under certain conditions, in its 28 formation some of the tautomeric indene compounds are 2g present. When these isomers are reacted in the presence of ., ~ .
`il 30 a base as in the reaction with glyoxylic acid, the same 1 indenyl anion is formed which reacts with glyoxylic acid ~J ~
.,:.' g _ .~ -,.
: ~ ,.":.. "", : , r ~ 15576IA
f~?"~ f,~ S
, 1 in the same way, ~i~iny the ind~ne compound. For example, 2 the Grignard o~ p-methylth.iobenzyl chloride or the Wittig re-; 3 agent of p-methylsulfinylbenzyl triphenylphosphonium chloride 4 is reacted with 5--fluoro-2-methyl-1-indanone under Grignard or Wittig conditions, respectively. In the case of the 6 Grignard reaction, the benzyl indene compound is obtained 7 directly; whereas with the Wittig reaction, one obtains for 8 the most part the benzylidene in~ane compound. In this 9 latter case, the benzylidene is isomerized to the benzyl com-pound under acid conditions by well known means for isomeriza-11 tion.
12 More specifically, the benzyl group is attached to 13 the indanona compound via a ~rignaxd or Wittig reaction under 14 well known conditions~ For example, in the Grignard reaction to metallic magnesium in absolute ether is added the appro-: j .
~ 16 priate benzyl halide (Cl, Br, F, I) tp-methylthiobenzyl halide . ~. ,!
17 or p-methylsulfinylbenzyl halidet and the reaction mixture heated preferabl~ from 25 to 35C. Although more or less 19 than an equimolar amount o~ magnesium may be used, it is 3~ 20 ad~antageous to use 3-6 ~old excess relative to the benzyl 21 halide. Although diethylether is usually used as the sol-22 vent, other ethers may be similarly used such as di-n-butyl, 23 diisopentyl ethers, anisole, cyclic ethers such as tetra-~: :
24~ hydropyran, 4-methyl-1,3-dioxane, d;hydropyran, tetrahydro-~ 2~5 furfuryl methyl ether, ethyl ether, furan and 2-ethoxy-;~ ~-~ 26 tetrahydrofuran. Tertiary amines such as dimethylaniline, ; ~ 27 hydrocarbons such as benzene and toluene, as well as ~ 28 many other type solvents described in the literature , ~ ~ :
29 can be also used~ The Grignard reagent thus prepared may be suitably used as is for reaction with 31 the indanone. The indanone and Grignard are admixed j . -;`,'1 ji 1~S76 1 (preferably indanone to Grignard) at a temperature of from 2 about 0C to the boiling point of the solvent and prefer~bly 3 20 to 35C. The concentrations of reactants are not criti 4 cal; however ~or best results, about equimolar quantities of each are used. The complex thus formed is reacted as 6 is usually done with Grignard reactions with an acid. In-7 organic mineral acids such as HCl, H2SO4 and phosphoric 8 acids may be used as well as organic or aliphatic acids 9 such as acetic, propionic or methanesulfonic. Usually, at - 10 least a 5-10% molar excess of acid to complex is used. It .:
11 is preferred to add the acid to the complex reaction mixture 12 usually as a dilute solution in water, although other 13 solvents for the acid may also be used such as alcohols, 14 ethers or aromatic hydrocarbons. The reaction temperature is usually 0 to 100C, although 20 to 40C is preferred.
16 In the Wittig reac~ion, for example, triphenyl-17 phosphine or a substituted triphenylphosphine is reacted 18 with the appropriate benzyl halide (p-methylthio or p-:.
19 methylsulfinylbenzyl halide) in the melt or in the pre-sence of suitable solvents to form the intermediate phos-21 phonium salt. Such solvents as (aromatic) benzene, nitro-22 benzene, xylene (ethers) diethyl ether, acetonitrile or -23 dimethylformamida, (aliphatic) nitromethaner formic acid, 24 acetic aoid and ethylacetate as well as many others described in the literature may be used. The preparation 26 of the phosphonium salt is carried out under temperatures 27 well known to the art such as from 0 to 200C and especially 28 25 to 75C , at atmospheric pressure as well as under 2~ pressure. The molar concentration of the triphenylphos-phine to ~he benzyl halide may suitably vary from 2 moles 31 to 1 mole and preferably 1~2 moles to 1 mole. The phos-32 phonium salt is not necessarily isolated and is converted ,, ~ ~49~5 l to the Wittig reagen~ employing either the organometallic ; 2 or alkoxide method. In the former method, phenyl lithium 3 or n-butyl lithium is the usual proton acceptor and di-4 ethyl ether or tetrahydrofuran, the solvent. In the latter method an alkali metal alkoxide may be used as the 6 proton acceptor and corresponding alcohols as the solvent~
7 The Wittig reagent is usually not isolated but `I 8 rather is allowed to react in the same reaction ~essel.
9 The reaction of the bases with the phosphonium salt is suitably carried out on about an equimolar basis, although 11 an excess of base may be advantageously used. The re-12 action may be carried out at a temperature of from 0C to . .
13 the boiling point of the solvent and preferably from 25 to ` ~ 14 50C~ AEter addition of ~.he base, the indanone compound is then added, suitably about equimolar wi h the Wittig re-16 agent, although more or less may be usedO
~ 17 The reaction may be carrie~ out at temperatures of from ;i 18 0C to the boiling point of the solvent but preferably 25 ., 19 to 50C until the reaction is substantially complete. The indene intermediate may then be isolated by standard ' :jt 21 techniques. In those cases wherein the Wittig reagent is 22 -first isolated, the reaction with the indanone may be 23 readily carried out in a variety of inert solvents. Solvents 24 such as ether~ benzene, ethylacetate, hexane or petroleum ether may be suitably used.
26 The 5-fluoro-2-methyl-l-indanone is prepared 27 from a ketone of the formula:
C - C - G
O
) . -~ ~ - 12 -.. ; .. . - , . . . . . . .
` 15576IA
$
1 wherein A is methyl or toyether with G forms methylidene:
2 B is hydrogen, methyl or halo (Cl, Br, F, I); G is 3 methyl, CH2R or together with A forms methylidene, wherein .
4 R is halo (Cl, Br, F, I), hydroxy, its ethers or esters ~such as from alkanols ~especially Cl 5 alkanols), alkanoic 6 acids ~especiall~r C2 5 alkanoic acids), aromatic acids 7 ~especial~y C7 9 aromatic acids), mineral acids, i.e., 8 methanol, propanol, acetic acid, propionic acid, methane 9 sulfonic acid, p-toluenesulfonic acid, phosphoric acid, and the like) or -N-(Cl 5 alkyl)2 especially methyl and 11 ethyl; and when A and G together is methylidene, B is ~ 12 methyl; when A and G are each methyl, B is halo; and when .',.! 13 A is methyl and B is hydrogen, G is CH2R; is reacted under 14 Friedel Crafts conditions to form 5-fluoro-2-methyl-1--~ 15 indanone. Preferably, the ketone starting material is 16 2-bromo-4'-fluoro-2-methylpropiophenone (when A and G are 17 each methyl and B is halogen) but may suitably also be 4'-18 fluoro-2-methylacrylophenone, 3-chloro-4'-fluoro-2-methyl-l 19 propiophenone, 4'-fluoro-3-hydroxy-2-methylpropiophenone . ~l or 3-dimethylamino-4'-fluoro-2-methylpropiophenone. The 21 reaction is suitably carried out under normal Friedel Crafts '~ 22 conditions. For example, the ketone is reacted in the pre-`'3, 23 sence of such Friedel Crafts catalysts as Lewis acids, 24 metal~alkyls and alkoxides, Bronsted acids, acidic oxides and sulfides, cation exchange resins, metathetic cation 26 ~orming agents and stable carbon.ium and related complexes.
27 Lewis acids such as those of the acid halide type ~metal 28 halides), i.e., aluminum chloride or bromide, BeC12, CdC12, 29 ZnC12, BF3, BC13, BBr3, GaC13, ~aBr3, TiC14, TiBr4, ZrC14, i~ 30SnC14, SnBr4, SbC15, SbC13, BiC13, FeC13 and UC14 may .'; ~;
.,~,, ~' ~ ~ 13 Z~
1 be suitably used. Also, when the ketone is the a or ~-halo~
2 isobutyrophenone, the metals p~r se may be used as catalysts, 3 since in the couxse of the reaction the halo compound reacts 4 with the metal forming the corresponding metal halide, 5 which in turn assists in furthering the reaction. This 6 class of Friedel Crafts catalysts is preferred and parti-7 cularly the use of an aluminum or iron halide. The metal ~; 8 alkyl and alkoxides which can be suitably used are~ for 9 example, aluminum or boron alkyls (methyl, ethyl, propyl) 10 or alkoxides ~methoxide, ethoxide or propoxide3. Bronsted 11 acids which c~n be suitably used are, for example, sulfuric, -`s 12 phosphoric, polyphosphoric, perchloric, chlorosulfonic, ~ 13 fluorosulfonic, alkyl and arylsulfonic (ethane, p-toluene~
~1 9 14 and related aromatic sulfonic acids~ as well as chloroacetic i
15 and trifluoroacetic acids. The acidic oxides and sulfides
16 useful as catalysts include a great variety of solid oxides :, ,i . . .
; 17 and sulfides. Of particular usefulness are aluminum, ~ 18 silica and mixtures of aluminum and silica, although . J~
` 19 catalysts other than silica-aluminum compositions such as 2 3' 25' Ti2' Th2' A12(S4)3~ A1203 . x Cr o ;~
2 3 Fe203, A1203 . CoO, A1203, MnO, A1203 . Vl O
22 Cr2o3 . Fe203, MoS2 or MoS3 may be also used. In addition, ~ 23 cation exchange resins which are solid acids are useful as `~1 24 catalyst, as well as metathetic aation forming agents such as anhydrous silver salts (AgC104, AgBF4, AgSbF6, AgPF6, ~ 26 AgAsF6 and Ag3PO4).
;~ 27 Although the concentration of Friedel Crafts cata-28 lyst is not critical, it is preferred to employ from 1.1 `?
29 to 2.0 moles of catalyst to one mole of ketone and pre-~,~ 30 ferably 1.4 to 1.8 moles per mole of ketone. The reaction ':' '!~
,, ~ .
,' , .:: ..
, .:i "'~` ~r :
.
1 is suitably carried out in a solvent which is normally 2 used for the Friedel Crafts reaction. Accordingly, such 3 organic solvents as CS2 7 fluorobenzene, polyhalogenated 4 aromatic hydrocarbon, nitrobenzene, aliphatic hydrocarbon, halogenated aliphatic hydrocarbons and nitroalkanes. The 6 reaction is carried out at a temperature of from about 0C
7 to about 150C and preferably 20 to 100C for a period of 8 time sufficient to substantially complete the reaction.
....
9 The ketone starting material is readily prepared ; '`` :
- 10 by condensing an appropri~te acid halide of the formula:
.:, ~ .;j A G
G - C - C - Z
B
11 wherein A, B and G are as previously described and Z is 12 halo, with fluorobenzene under Friedel Crafts conditions 13 as described previously. Further, if desired, the acid 14 halide may be condensed with the fluorobenzene to form the ketone and in situ go directly to the 5-fluoro-2-16 methyl l~indanone. In the event that this procedure is
; 17 and sulfides. Of particular usefulness are aluminum, ~ 18 silica and mixtures of aluminum and silica, although . J~
` 19 catalysts other than silica-aluminum compositions such as 2 3' 25' Ti2' Th2' A12(S4)3~ A1203 . x Cr o ;~
2 3 Fe203, A1203 . CoO, A1203, MnO, A1203 . Vl O
22 Cr2o3 . Fe203, MoS2 or MoS3 may be also used. In addition, ~ 23 cation exchange resins which are solid acids are useful as `~1 24 catalyst, as well as metathetic aation forming agents such as anhydrous silver salts (AgC104, AgBF4, AgSbF6, AgPF6, ~ 26 AgAsF6 and Ag3PO4).
;~ 27 Although the concentration of Friedel Crafts cata-28 lyst is not critical, it is preferred to employ from 1.1 `?
29 to 2.0 moles of catalyst to one mole of ketone and pre-~,~ 30 ferably 1.4 to 1.8 moles per mole of ketone. The reaction ':' '!~
,, ~ .
,' , .:: ..
, .:i "'~` ~r :
.
1 is suitably carried out in a solvent which is normally 2 used for the Friedel Crafts reaction. Accordingly, such 3 organic solvents as CS2 7 fluorobenzene, polyhalogenated 4 aromatic hydrocarbon, nitrobenzene, aliphatic hydrocarbon, halogenated aliphatic hydrocarbons and nitroalkanes. The 6 reaction is carried out at a temperature of from about 0C
7 to about 150C and preferably 20 to 100C for a period of 8 time sufficient to substantially complete the reaction.
....
9 The ketone starting material is readily prepared ; '`` :
- 10 by condensing an appropri~te acid halide of the formula:
.:, ~ .;j A G
G - C - C - Z
B
11 wherein A, B and G are as previously described and Z is 12 halo, with fluorobenzene under Friedel Crafts conditions 13 as described previously. Further, if desired, the acid 14 halide may be condensed with the fluorobenzene to form the ketone and in situ go directly to the 5-fluoro-2-16 methyl l~indanone. In the event that this procedure is
17 desired additional Friedel Crafts catalyst is employed "~
18 su~f~icient to carry out the two steps. `~
19 ~ he following examples are given by way of
20~ illustration.
~ 21~ EXAMP~E 1 ;~ ~ 22 4'-Fluoro-3-hydroxy-2-methylpro~iophenone -~
23~ ~ A mix~ure of 45.7 g. (0.3 moles) of 4'-fluoro-24 propiophenone, 9 g. (0.3 moles) of paraformaldehyde, 4 g.
,.,,:~ ~: . .
!~ ~ ' 24 ~0.03 mole) of anhydrous potassium carbonate and 200 ml.
~ 25 of methyl alcohol is stirred at 35C for two days. The . ~ :
26 reaction is quenched in water and acidified with hydro-27 chloric acid. The product is extracted into benzene.
.:~ ' ~ ' ~ 15 -~iir~ s 1 The benzene layer is washed with water and concentrated 2 in vacuo to give 4'-fluoro-3-hydroxy-2-methylpropiophenone.
3 EX~MPLE 2 4 5-Fluoro-2-me-thyl-1-indanone from 4'-fluoro-3-hydroxy-2-methylpropiophenone :
6 A mixture of 18.2 g. (0.10 mole) of 4'~fluoro-7 3-hydroxy-2-methylpropiophenone and 12 g. of phosphorous 8 pentoxide in 100 mlO of xylene i5 refluxed for one hour.
~; 9 The reaction is cooled, water is added and the xylene layer is washed with aqueous sodium hydroxide and water. The 11 organic layer is then concentrated in vacuo to give 5-fluoro-12 2-methyl-1-indanone.
:: _ i 14 2-Bromo-4'-fluoro-2-methylpropiophenone "'1 - --; 15 A slurry of 14 g. (0.105 mole) of anhydrous ~, aluminum chloride in 14.4 g. (0.150 mole) of fluoro-i 17 benzene and 24 ml. of carbon disulfide is cooled to 15C.
18 To it is added 23.8 g. (0.100 mole) of a-bromoisobutyryl ~1~ 19 bromide over 10-15 minutes at 15-20C. The reaction is stirred for ~ive minutes at 20C and then quenched on ice.
~ 21~ EXAMP~E 1 ;~ ~ 22 4'-Fluoro-3-hydroxy-2-methylpro~iophenone -~
23~ ~ A mix~ure of 45.7 g. (0.3 moles) of 4'-fluoro-24 propiophenone, 9 g. (0.3 moles) of paraformaldehyde, 4 g.
,.,,:~ ~: . .
!~ ~ ' 24 ~0.03 mole) of anhydrous potassium carbonate and 200 ml.
~ 25 of methyl alcohol is stirred at 35C for two days. The . ~ :
26 reaction is quenched in water and acidified with hydro-27 chloric acid. The product is extracted into benzene.
.:~ ' ~ ' ~ 15 -~iir~ s 1 The benzene layer is washed with water and concentrated 2 in vacuo to give 4'-fluoro-3-hydroxy-2-methylpropiophenone.
3 EX~MPLE 2 4 5-Fluoro-2-me-thyl-1-indanone from 4'-fluoro-3-hydroxy-2-methylpropiophenone :
6 A mixture of 18.2 g. (0.10 mole) of 4'~fluoro-7 3-hydroxy-2-methylpropiophenone and 12 g. of phosphorous 8 pentoxide in 100 mlO of xylene i5 refluxed for one hour.
~; 9 The reaction is cooled, water is added and the xylene layer is washed with aqueous sodium hydroxide and water. The 11 organic layer is then concentrated in vacuo to give 5-fluoro-12 2-methyl-1-indanone.
:: _ i 14 2-Bromo-4'-fluoro-2-methylpropiophenone "'1 - --; 15 A slurry of 14 g. (0.105 mole) of anhydrous ~, aluminum chloride in 14.4 g. (0.150 mole) of fluoro-i 17 benzene and 24 ml. of carbon disulfide is cooled to 15C.
18 To it is added 23.8 g. (0.100 mole) of a-bromoisobutyryl ~1~ 19 bromide over 10-15 minutes at 15-20C. The reaction is stirred for ~ive minutes at 20C and then quenched on ice.
21 The product is extracted into chloroform. The chloroform -~; 22 layer is washed with aqueous sodium bicarbonate, dried over 23 anhydrous~sodium sulfate and concentrated to give 2-bromo 24 4'-fluoro-2-methylpropiophenone.
i ~j 26 5-Fluoro-2-methyl-1-indanone from 2-bromo-4'-1uoro-2-i~ 27 methylpropiophenone "~
28 To a slurry o 120.2 g. (0.90 mole) of anhydxous ~1~ 29 aluminum chloride in 54 ml. of carbon disulfide is added .;:`~
122.6 g. (0.50 mole) of 2-bromo 4'-fluoro-2-methylpropio-31 phenone at 15-20C over one hour. The mixture is warmed :, ;~
~,,,, :',J ' - 16 -,. :.. :, . . - . . . - . . . : . ~ ....
;,t~ 15 576 IA
-Lff~5 :, 1 to 50OC ov~r one hour, stir~ed at 50C for three hours and .:
2 quenched in ice~ The product is extracted into toluene.
3 The toluene layer is washed with aqueous sodium hydroxide 4 and water and ~oncentrated _n vacuo to give 5-fluoro-2-methyl-l-indanone.
. . .
7 4'-Fluoro-2-methylacrylo~henone 8 A slurry of 29.4 g. (0.220 mole) of anhydrous 9 aluminum chloride in 38.4 g. (0.40 mole) of fluorobenzene ., 10 under nitrogen is cooled to 15C. Methylacryl chloride ,~ 11 (21.9 g., 0.200 mole) is then added dropwise over 30 12 minutes while holding the tempexature at 15-20C. The ,,. ~
s 13 mixture is warmed to 30C over 10 minutes, stirred at 14 30C for 10 minutes and quenched in ice. The product is :
,"',''A 15 extracked into hexane. The hexane layer is dried over ~ 16 anhydrous sodium sulfate and concentrated ln vacuo to give ;~ 17 4'-fluoro-2-methylacrylophenone.
~; 18 EXAMPLE 6 `;,~ 19 5-Fluoro-2-methyl-1-indanone from 4'-fluoro-2-methyl-.13 20 acrylophenone .: I . . . .. _ .. . _ . .
; ,~
`~1 21 Fifty grams (0.30 moles) of 4'-fluoro-2~methyl-j~, 22 acrylophenone is added to a slurry of 60.1 g. (0.45 moles) ~. ~
23 of anhydrous aluminum chloride in 27 ml. of carbon di~
24 suLfide at 20-25C over one hour. The mixture is heated to 45C over one hour and stirred at 45C for one hour.
26 The reaction is quenched in ice. The oily aqueous layer 27 is extracted with toluene. The toluene layer is washed 28 with aqueous sodium hydroxide and water and concentrated i~ 29 in vacuo to give 5-fluoro-2-methyl-1-indanone.
.` ' ~ , $ `
"~i ... ~ , !
~ - ~ 17 _ 2 3-Chloro-4'-fluoro-2-methylpro~ enone 3 To a slurry of 22.7 g. (0.17 mole) of anhydrous 4 aluminum chloride and 9.6 g. (0.10 mole) of fluorobenzene ' 5 is added 14.1 g. (0.10 mole) of ~-chloroisobutyrylchloride 6 over 30 minutes at 20-25C. The mixture is aged for 7 30 minutes at 20-25C and then quenched in ice. The 8 product is extracted into hexane. The hexane layer is - 9 dried over anhydrous sodium sul~ate and concentrat~d in vacuo to give 3~chloro-4'-fluoro~2-methylpropiophenone.
~, 11 EXAMP1E 8 , _ ~ 12 5-Fluoro-2-methyl-l-indanone from 3-chloro-4'-fluoro-2--' 13 methylpropiophenone .
14 Ten grams (O.OS mole) of 3-chloro-4'-fluoro-2-methylpropiophenone is added to 20 ml. of concentrated sul-. . .~
16 furic acid at 20-25C and the mixture is warmed to 50C. -~
l 17 After stirring for three hours at 5~C, the reaction is ;;I 18 quenched in ice. The product is extracted into hexane.
19 The hexane layer is concentrated ln vacuo to give 5-fluoro-2-methyl-l-indanone.
1 .
`~ 21 EXAMPLE 9 ~.
i ~j 26 5-Fluoro-2-methyl-1-indanone from 2-bromo-4'-1uoro-2-i~ 27 methylpropiophenone "~
28 To a slurry o 120.2 g. (0.90 mole) of anhydxous ~1~ 29 aluminum chloride in 54 ml. of carbon disulfide is added .;:`~
122.6 g. (0.50 mole) of 2-bromo 4'-fluoro-2-methylpropio-31 phenone at 15-20C over one hour. The mixture is warmed :, ;~
~,,,, :',J ' - 16 -,. :.. :, . . - . . . - . . . : . ~ ....
;,t~ 15 576 IA
-Lff~5 :, 1 to 50OC ov~r one hour, stir~ed at 50C for three hours and .:
2 quenched in ice~ The product is extracted into toluene.
3 The toluene layer is washed with aqueous sodium hydroxide 4 and water and ~oncentrated _n vacuo to give 5-fluoro-2-methyl-l-indanone.
. . .
7 4'-Fluoro-2-methylacrylo~henone 8 A slurry of 29.4 g. (0.220 mole) of anhydrous 9 aluminum chloride in 38.4 g. (0.40 mole) of fluorobenzene ., 10 under nitrogen is cooled to 15C. Methylacryl chloride ,~ 11 (21.9 g., 0.200 mole) is then added dropwise over 30 12 minutes while holding the tempexature at 15-20C. The ,,. ~
s 13 mixture is warmed to 30C over 10 minutes, stirred at 14 30C for 10 minutes and quenched in ice. The product is :
,"',''A 15 extracked into hexane. The hexane layer is dried over ~ 16 anhydrous sodium sulfate and concentrated ln vacuo to give ;~ 17 4'-fluoro-2-methylacrylophenone.
~; 18 EXAMPLE 6 `;,~ 19 5-Fluoro-2-methyl-1-indanone from 4'-fluoro-2-methyl-.13 20 acrylophenone .: I . . . .. _ .. . _ . .
; ,~
`~1 21 Fifty grams (0.30 moles) of 4'-fluoro-2~methyl-j~, 22 acrylophenone is added to a slurry of 60.1 g. (0.45 moles) ~. ~
23 of anhydrous aluminum chloride in 27 ml. of carbon di~
24 suLfide at 20-25C over one hour. The mixture is heated to 45C over one hour and stirred at 45C for one hour.
26 The reaction is quenched in ice. The oily aqueous layer 27 is extracted with toluene. The toluene layer is washed 28 with aqueous sodium hydroxide and water and concentrated i~ 29 in vacuo to give 5-fluoro-2-methyl-1-indanone.
.` ' ~ , $ `
"~i ... ~ , !
~ - ~ 17 _ 2 3-Chloro-4'-fluoro-2-methylpro~ enone 3 To a slurry of 22.7 g. (0.17 mole) of anhydrous 4 aluminum chloride and 9.6 g. (0.10 mole) of fluorobenzene ' 5 is added 14.1 g. (0.10 mole) of ~-chloroisobutyrylchloride 6 over 30 minutes at 20-25C. The mixture is aged for 7 30 minutes at 20-25C and then quenched in ice. The 8 product is extracted into hexane. The hexane layer is - 9 dried over anhydrous sodium sul~ate and concentrat~d in vacuo to give 3~chloro-4'-fluoro~2-methylpropiophenone.
~, 11 EXAMP1E 8 , _ ~ 12 5-Fluoro-2-methyl-l-indanone from 3-chloro-4'-fluoro-2--' 13 methylpropiophenone .
14 Ten grams (O.OS mole) of 3-chloro-4'-fluoro-2-methylpropiophenone is added to 20 ml. of concentrated sul-. . .~
16 furic acid at 20-25C and the mixture is warmed to 50C. -~
l 17 After stirring for three hours at 5~C, the reaction is ;;I 18 quenched in ice. The product is extracted into hexane.
19 The hexane layer is concentrated ln vacuo to give 5-fluoro-2-methyl-l-indanone.
1 .
`~ 21 EXAMPLE 9 ~.
22 3-Dimethylamino-4'-fluoro-2-methylpropiophenone
23 A mixture of 15.2 g. (0.10 mole) of 4'-fluoro-..i~
; ~; 24 propiophenone, 8.2 g. (0.10 mole) of dimethylamine hydro-'"-1 ' 25 chloride, 3.6 g. (0.12 mole) of paraformaldehyde in 20 ml.
~ 26 of absolute alcohol was stirred at 95-100C for three .: ~ :
27 hours. The mixture is cooled and the precipitated product ;i~ 28 is filtered. The product is dissolved in water, made `~3 29 alkaline with sodium hydroxide. The free base is extracted ;~ 30 into ether. The ether layer is dried over anhydrous sodium : ,i 31 sulfate and concentrated in vacuo to give 3-dimethylamino-:: 3 ~
: ....................................................................... . .
.~:' :1 15576I~
1. 4'-fluoro-2-methylpropiophenone.
3 5-Fluoro-2-methyl-1-ind~none from 3-dimethylamino-4'-4 fluoro_2-methylpropiophenone :
S A mixture of 42 g. (0.20 mole~ of 3-dimethylamino-- 6 4'-fluoro-2-me hylpropiophenone and loO ml. of concentrated 7 sulfuric acid is warmed to 90C over one hour and stirred `~ 8 at 90C ~or two hours. The re~ction is cooled and 9 quenched in ice and the product extracted into toluene.
The toluene layer is washed with aqueous sodium hydroxide 11 and water and concentrated in vacuo to give 5-fluoro-2-methyl-12 l-indanone.
~;~ 13 EXAMPLE 11 .,.~ . .
l 14 5-Fluoro-2-methyl-1-indanone from fluorobenze~e and- a-: lS bromoisobutyryl bromide ~` 16 To a slurry of 120.2 g. (0.90 mole) of anhydrous 17 al~minum chloride in 54 ml. of carbon disulfide and 51.4 g.
18 (0.535 mole) of fluorobenzene under nitrogen is added ,'~ 19 115 g. (0.50 mole) of a-bromoisobutyryl bromide. The addition is accomplished at 15-20C over 75 minutes. The 21 reaation is warmed to 50C over 75 minutes, stirred at 22 50C for 3 1/2 hours and then quenched in ice. Toluene 23 ~is~added to extract the product. The toluene layer is
; ~; 24 propiophenone, 8.2 g. (0.10 mole) of dimethylamine hydro-'"-1 ' 25 chloride, 3.6 g. (0.12 mole) of paraformaldehyde in 20 ml.
~ 26 of absolute alcohol was stirred at 95-100C for three .: ~ :
27 hours. The mixture is cooled and the precipitated product ;i~ 28 is filtered. The product is dissolved in water, made `~3 29 alkaline with sodium hydroxide. The free base is extracted ;~ 30 into ether. The ether layer is dried over anhydrous sodium : ,i 31 sulfate and concentrated in vacuo to give 3-dimethylamino-:: 3 ~
: ....................................................................... . .
.~:' :1 15576I~
1. 4'-fluoro-2-methylpropiophenone.
3 5-Fluoro-2-methyl-1-ind~none from 3-dimethylamino-4'-4 fluoro_2-methylpropiophenone :
S A mixture of 42 g. (0.20 mole~ of 3-dimethylamino-- 6 4'-fluoro-2-me hylpropiophenone and loO ml. of concentrated 7 sulfuric acid is warmed to 90C over one hour and stirred `~ 8 at 90C ~or two hours. The re~ction is cooled and 9 quenched in ice and the product extracted into toluene.
The toluene layer is washed with aqueous sodium hydroxide 11 and water and concentrated in vacuo to give 5-fluoro-2-methyl-12 l-indanone.
~;~ 13 EXAMPLE 11 .,.~ . .
l 14 5-Fluoro-2-methyl-1-indanone from fluorobenze~e and- a-: lS bromoisobutyryl bromide ~` 16 To a slurry of 120.2 g. (0.90 mole) of anhydrous 17 al~minum chloride in 54 ml. of carbon disulfide and 51.4 g.
18 (0.535 mole) of fluorobenzene under nitrogen is added ,'~ 19 115 g. (0.50 mole) of a-bromoisobutyryl bromide. The addition is accomplished at 15-20C over 75 minutes. The 21 reaation is warmed to 50C over 75 minutes, stirred at 22 50C for 3 1/2 hours and then quenched in ice. Toluene 23 ~is~added to extract the product. The toluene layer is
24 ~washed with aqueous sodium hydroxide and water and concen-. s. ~
trated~in vacuo to give 79 g. (96%) of 5-fluoro-2-methyl-;26 l-indanone. `~
27 ~ EXAMPLE 12 28 5-Fluoro-2-methyl-1-(p-methylthiobenzyl)-indene 2g Twenty-five grams (1.04 moles) of magnesium turnings were placed in a dried flask under N2 with , 1 9 -,'i ~ s~ 15576IA
, .
S
1 400 ml. of ether~ Ten ml. of 0.05 molar p-rnethylthioben~yl 2 magnesium chloride in ether i5 added and the mixture is 3 warmed to 30C. About 2-3% o~ 39.7 y. (0.23 moles) of 4 p-methylthiobenzyl chloride in 75 ml. of toluene is added.
A~ter 3-5 minutes of stirring an exotherm to 32-33C occurs 6 siynifying initiation of the reaction. After aging for 7 5 minutes, the rest of the benzyl chloride is added drop-` 8 wise over 90 minutes. The reaction is aged or 30 minutes 9 with stirring. 5-Fluoro-2-methyl-1-indanone (32.6 g., 0.199 mole) is added dropwise o~er 45 minutes. After 11 aging for 30 minutes, the milky supernatant mixture is 12 decanted from the maynesium. The flask and residual 13 magnesium are rinsed with toluene. The reaction is then , 14 quenched by the addition of 120 ml. of 3N sulfuric acid.
The lower layer is discarded. To the organic layer is 16 added 80 ml. of 1:10 concentrated sulfuric acid, acetic 17 acid and the two-phase mixture, stirred vigorously for one 18 hour and water (100 ml.) is added. The bottom layer is 19 discarded and the organic layer is washed with 100 ml. of water and 200 ml. of 2N sodium hydroxide. After a final 21 water wash the organic layer is concentrated to give 5-fluoro-,: ~, ;~ 22 2-me~hyl-1-(p-methylthiobenzyl)-indene. Similarly, when ~:
23 p-methylsul~inylbenzyl chloride is used in place o~ p-24 methylthiobenzYl chloride in the above example, the corresponding p-methylsulfinylbenzyl indene is obtained.
:i:
i~ 26 EXAMPLE 13 :. ~ _.
27 ~-Methylthi ~ iphenylphosphonium chloride ~ 28 17.3 g. of p-methylthiobenzyl chloride is added il 29 to 28 g. of triphenylphosphine in 80 ml. of benzene.
The reaction was heated for 4 hours, then cooled and the ,, ,, I ~ - 20 -, ~ 15576IA
1 product r p~methylthiobenzyltriphenylphosphorlium chloride, 2 was collected by filtr~tion. There is obtained 19 g., melting point 257-258OC.
4 In a similar manner, when p-methylsulfinyl-benzyl chloride is used, the product is p-methylsulfinyl-6 benzyltriphenylphosphonium chloride~ melting point 258-! 7 262C with gasing.
8 EX~MPL 14 9 5-Fluoro 2 methy1-1-(p-m hylthiobenzyl)-indene A. 5-_1 o o-2-me~ e~__thylthiobenzylidene)-indane .
11 169 Mg. (1.5 mm) of potassium t-butoxide is 12 dissolved in 2 ml. of DMSO and treated with 651 mg.
, 13 (1.5 mm) of p-methylthiobenzyltriphenylphosphQnium `~ 14 chloride dissolved in 1 ml. of DMSO. To this solution 1 15 is added 270 mg. (1.65 mm) of ~-fluoro-2-methyl-1-indanone ~f 16 in 2 ml. of DMSO. The solution is heated at 75C for 15.5 `~i 17 hours. Benzene and water are added and the benæene layer 18 is washed five times with water. The benzene layer is 19 dried over Na2SO4 and evaporated to dryness under vacuum.
The weight is 915.6 my. This material is eluted through ` 21 8 g. of silica gel with benzene to remove triphenylphos-22 phine oxide. The eluate weights 372 mg. after removal of 23 solvent. This is rechromatographed through 15 g. of 24 silica gel using hexane and 95.9 mg. of 5-fluoro-2-methyl-l-(p-methylthiobenzylidene)-indane is isolated, melting 26 point 67-70C.
~; 27 B~ ~
28 50 M~.~of the benzylidene compound from A above 29 is mixed with 1 ml. of ace~ic acid containing 100 mg. of ~ 30 sulfuric acid and the reaction mixture stirred for 1 hour j~ 31 at room temperature. The mix~ure is then diluted with :
, ~:
, . . .
~3~
1 water a~d extracted with ethex. The ether extract is 2 concentrated in acuo to ~ive the ~ubject compound.
3 Similarly, when the p-methylsulfinylbenzyl 4 triphenylphosphonium chloride is used, the corresponding p-methylsulfinylbenzyl indene compound is obtained.
6 EXA~'LE 15 ~ 7 5-Fluoro-2-m ~
- 8 500 mgO (1.755 mm) of 5-fluoro-2-methyl-1-- 9 (p-methylthiobenzyl)-indene is dissolved in 5 ml. of ~ 10 chloroform. To this solution is added 30% hydrogen `;~ 11 peroxide ~equivalent to 2.645 mm). The reaction mixture ` 12 is aged for one hour at room tem~erature followed by the ,~
13 addition of 5 ml. of glacial acetic acid and aged for 14 an additional hour. The reaction mixture is then diluted with 25 ml. of 1:1 benzene-ether and extracted with 6 x 16 25 ml. of 3~ a~ueous sodium chloride. The solution is 17 then dried over sodium sulfate and evaporated in vacuo 18 to yield an oil. Recrystallization from ice-cold iso-9 propanol yives 5-fluoro-2-methyl-1-(p-methylsulfinyl benayl)-indene~
22 5-Fluoro-2-methyl~ p-methylthioben~yl)-indenylidene-23 3-acetic_ cid _ _ _ 24 To 41.8 g. (147 mmole) of the preceeding indene (from Example 12) is added 150 mi. of methanolic Triton B
~ .:
26 solution~ (53.2 g., dry basis; 317.5 mmole) and the batch, 27 under a nitrogen atmosphere, is brought to 35C. 14.63 G.
1 28 glyoxylic acid (198 mmole) is added and the batch, which ,~ 29 warms to 50-55C is aged one hour at 50C. It is then ~ 30 diluted with 250 ml~ of water and acidified with dilute :3 ! 22 .
,-. ,. . ~ . . .
.,~''P'~
sulfuric acid~ The product obtained in 90~ yield is re-2 crystallized to give the pure subjec~ product, melting 3 point 185.5-188C~ -4 When sodium hydroxide and tetramethylammonium chloride or tetramethylammonium hydroxide is used in . .
6 place of Triton B in the above example, the indenylidene- -, 7 3-acetic acid is obtained.
` 8 Similaxly, when 5-~luoro-2-methyl-1-(p-methyl-9 sulfinylbenzyl)indene is used in place of the corresponding ;- ~
10 methylthio compound in the above example, there is obtained Ll 5-~luoro-~-methyl-1-(p-methylsulfinylbenzyl)-ind~nylidene-12 3-acetic acid.
, ~ ~ 13 EXAMPLE 17 ,:.
14 5-Fluoro-2-methyl-1-(p-methylthiobenzylidene)-indene-3-15 acetic acid ___ _ __ 16 A suspension of 34.2 g. of 5-fluoro-2-methyl~
: i,i ~i 17 1-(p-methylthiobenzyl)-indenylidene -3-acetic acid (~rom ~; 18 Example 16) in 342 ml. o~ glacial acetic acid and 137 ml.
19 o concentrated ~Cl is stirred under a nitrogen atmosphere 20 at 90C for 10 hours. The reaction is cooled over 2 to , . , ' . , l 21 3 hours -to room temperature and aged an additional 3 hours .. . .
~,4'~,~ 22 at 20-25~. The batch is filtered, washed with 70:30 ~; , ,,:
23 acetic acid-water (ca. 100 ml.) then water-washed to remove ~ 24 excess acid. There is obtained 93% of product, melting ;`1 25 point 180-183C.
`~1 26 Similarly when 5-fluoro-2-methyl-1-(p-methylsul-!''.'~ 27 finylbenz~yl)-indenylidene~3-acetic acid is used in the .. .. .
28 above example in place of the corresponding methylthio 29 compound, there i5 obtained 5-fluoro-2-methyl-l~(p-methyl-,'s', ;3 t,;,,~
~`i` ;
, .j 1 sulfinylbenzylidene~-indene-3-acetic acid. The reaction 2 may be conductecl in an aprotic solvent such as 1,2-di-3 chloroethane under 100 p.~.i.g. of HCl gas at 50-100C.
5~Fluoxo-2-methyl-1-(p-methylsulfinylbenzylidene)-indene-6 _-acet c_acid _ __ _ 7 Seventeen grams (50 mmole) of the produc~ from 8 Example 17 is stirred in 94 ml. of chloroform and 40 ml.
9 of acetic acid under nitrogen and the temperature brought to 30C. To this slurry is added 5.3 ml. of 9.6N a~ueous 11 H2O2 (51 mmole) over one minute. The temperature is 12 brought to 35C. The batch is aged ~ total of 6 hours, 13 maintaining 35C internal temperature. After the age 14 period, 125 ml. of water is added and the C~CL3 layer con-centrated to a small volume in vacuo. The residue is 16 crystallized from 75 ml. of ethanol and the slurry cooled 17 to 0-5C and aged at 0-5C. The product is filtered and 18 washed with 15 ml. of cold (0-5C) 2BA ethanol and dried 19 in vacuo at 80C. The product weighs 16.3 g. (92%), . _ melting point 183-185C.
21 Similarly, when sodium periodate or potassium . '!
22 hypochlorite is used in place of hydro~en peroxide in , 23 the above example/ there is obtained the desired compound.
~ 4 EXAMPLE 19 :i:
`.t 25 2-Dimethylarninomethyl-4'-fluoropropiophenone ~, 26 A slurry of 14 g. (0.105 mole) of anhydrous 27 aluminum chloride in 14.4 g. (0.150 mole) of fluorobenzene '~ 28 and 24 ml. of carbon disulfide is cooled to 15C. To it 29 is added 0.100 mole of a-(dimethylaminomethyl)propionyl ;
bromide hydxobromide over 10-15 minutes at 15-20C. The ~, 31 reaction is stirred for five minutes at 20C and then 3 32 quenched on ice. The product is ext acted into chlorofo~n.
:i ~ 15576IA
: , 1 The chloroEorm layer is washed wi.h aqueous sodium bicar-2 bonate, dried over anhydrous sodium sulfate a~d concentrated 3 to give 2-bromo-4'-fluoro-2-methylpropiophenone.
:
; 4 EX~MPLE 20 5-Fluoro-2-methyl-1-(p-methylthiobenzyl)-inde~e 6 13 . 44 Grams ( O . 56 moleJ of magnesium turnings 7 are placed in a dried flask under N2 with 125 ml. of 8 ether and a crystal of iodine. Six ml. of 65 ml. solution 9 of 24.2 g. (0.14 mole) of p-methylthiobenzyl chloride in ether is added. After 3 to 5 minutes of stirring the 11 iodine color disappears and the reaction begins. ~fter 12 agil~g for 5 minutes, the rest of the benzyl chloride is 13 added dropwise over 45 minutes. It is rinsed in with 14 10 ml. of ether and the reaction aged for 2 hours with : l ~tirring. 21 Grams (0.128 mole) of 5-fluoro-2-methyl-1-.
16 indanone dissolved in 50 ml. of ether is added dropwise 17 over 30 minutes. After aging for 1 hour, the milky super-18 natent mixture is decanted from the magnesium into 100 ml.
19 of acetic acid. The flask and residual magnesium are rinsed into the acid solution with 4 x 50 ml. o~ benzene.
21 Two hundred ml. o water are added, the layers are 22 s-eparated and the organic layer is washed with 5 x 200 ml.
23 water. It is stripped to dryness after drying over 24 Na2SO4. The crude reaction product is crystallized from --hexane to give pure 5-fluoro-2-methyl-1-(p-methylthio-26 benzyl~-indene, melting point 58-59C.
28 5-Fluoro-2-methyl-1-(p-methylthiobenzylidene)-indene-3-29 acetic acid _ A suspension of 34 grams of 5-fluoro-2-methyl~
31 (p-methylthiobenzyl)-indenylidene-3 acetic acid in 150 ml.
32 of ethylene dichloride is heated to 70C in a glass .
,~ .
~ ~ 15576IA
1 lined autoclave. Anhydrous hydrogen chloride is admitted 2 until the preSsUre reaches 95 pound.-i~ The reaction is 3 stirred under these conditions for 10 hours and the excess 4 gas is then vented. The product slurried is cooled to 0-5C and after one hour is filtered and washed with 6 fresh ethylene dichloride. The yield product is 80~i.
.~,. .
. i :'`' ;.~'`
:. }
: . ~
..J
: .i .~ ~, .
i3 :.'.~ :
q , j ~! :
: ~ .
'';~ : -, 1 ~' .
.'~1~ .
.~ , ` .
.,I' :
.3 ;"`~
j~, ' ' ~
'. ~ '',' .'~ :
~,'1 ' '~' : ` '' "`~ ;.
;''''.' ~
!
: .l
trated~in vacuo to give 79 g. (96%) of 5-fluoro-2-methyl-;26 l-indanone. `~
27 ~ EXAMPLE 12 28 5-Fluoro-2-methyl-1-(p-methylthiobenzyl)-indene 2g Twenty-five grams (1.04 moles) of magnesium turnings were placed in a dried flask under N2 with , 1 9 -,'i ~ s~ 15576IA
, .
S
1 400 ml. of ether~ Ten ml. of 0.05 molar p-rnethylthioben~yl 2 magnesium chloride in ether i5 added and the mixture is 3 warmed to 30C. About 2-3% o~ 39.7 y. (0.23 moles) of 4 p-methylthiobenzyl chloride in 75 ml. of toluene is added.
A~ter 3-5 minutes of stirring an exotherm to 32-33C occurs 6 siynifying initiation of the reaction. After aging for 7 5 minutes, the rest of the benzyl chloride is added drop-` 8 wise over 90 minutes. The reaction is aged or 30 minutes 9 with stirring. 5-Fluoro-2-methyl-1-indanone (32.6 g., 0.199 mole) is added dropwise o~er 45 minutes. After 11 aging for 30 minutes, the milky supernatant mixture is 12 decanted from the maynesium. The flask and residual 13 magnesium are rinsed with toluene. The reaction is then , 14 quenched by the addition of 120 ml. of 3N sulfuric acid.
The lower layer is discarded. To the organic layer is 16 added 80 ml. of 1:10 concentrated sulfuric acid, acetic 17 acid and the two-phase mixture, stirred vigorously for one 18 hour and water (100 ml.) is added. The bottom layer is 19 discarded and the organic layer is washed with 100 ml. of water and 200 ml. of 2N sodium hydroxide. After a final 21 water wash the organic layer is concentrated to give 5-fluoro-,: ~, ;~ 22 2-me~hyl-1-(p-methylthiobenzyl)-indene. Similarly, when ~:
23 p-methylsul~inylbenzyl chloride is used in place o~ p-24 methylthiobenzYl chloride in the above example, the corresponding p-methylsulfinylbenzyl indene is obtained.
:i:
i~ 26 EXAMPLE 13 :. ~ _.
27 ~-Methylthi ~ iphenylphosphonium chloride ~ 28 17.3 g. of p-methylthiobenzyl chloride is added il 29 to 28 g. of triphenylphosphine in 80 ml. of benzene.
The reaction was heated for 4 hours, then cooled and the ,, ,, I ~ - 20 -, ~ 15576IA
1 product r p~methylthiobenzyltriphenylphosphorlium chloride, 2 was collected by filtr~tion. There is obtained 19 g., melting point 257-258OC.
4 In a similar manner, when p-methylsulfinyl-benzyl chloride is used, the product is p-methylsulfinyl-6 benzyltriphenylphosphonium chloride~ melting point 258-! 7 262C with gasing.
8 EX~MPL 14 9 5-Fluoro 2 methy1-1-(p-m hylthiobenzyl)-indene A. 5-_1 o o-2-me~ e~__thylthiobenzylidene)-indane .
11 169 Mg. (1.5 mm) of potassium t-butoxide is 12 dissolved in 2 ml. of DMSO and treated with 651 mg.
, 13 (1.5 mm) of p-methylthiobenzyltriphenylphosphQnium `~ 14 chloride dissolved in 1 ml. of DMSO. To this solution 1 15 is added 270 mg. (1.65 mm) of ~-fluoro-2-methyl-1-indanone ~f 16 in 2 ml. of DMSO. The solution is heated at 75C for 15.5 `~i 17 hours. Benzene and water are added and the benæene layer 18 is washed five times with water. The benzene layer is 19 dried over Na2SO4 and evaporated to dryness under vacuum.
The weight is 915.6 my. This material is eluted through ` 21 8 g. of silica gel with benzene to remove triphenylphos-22 phine oxide. The eluate weights 372 mg. after removal of 23 solvent. This is rechromatographed through 15 g. of 24 silica gel using hexane and 95.9 mg. of 5-fluoro-2-methyl-l-(p-methylthiobenzylidene)-indane is isolated, melting 26 point 67-70C.
~; 27 B~ ~
28 50 M~.~of the benzylidene compound from A above 29 is mixed with 1 ml. of ace~ic acid containing 100 mg. of ~ 30 sulfuric acid and the reaction mixture stirred for 1 hour j~ 31 at room temperature. The mix~ure is then diluted with :
, ~:
, . . .
~3~
1 water a~d extracted with ethex. The ether extract is 2 concentrated in acuo to ~ive the ~ubject compound.
3 Similarly, when the p-methylsulfinylbenzyl 4 triphenylphosphonium chloride is used, the corresponding p-methylsulfinylbenzyl indene compound is obtained.
6 EXA~'LE 15 ~ 7 5-Fluoro-2-m ~
- 8 500 mgO (1.755 mm) of 5-fluoro-2-methyl-1-- 9 (p-methylthiobenzyl)-indene is dissolved in 5 ml. of ~ 10 chloroform. To this solution is added 30% hydrogen `;~ 11 peroxide ~equivalent to 2.645 mm). The reaction mixture ` 12 is aged for one hour at room tem~erature followed by the ,~
13 addition of 5 ml. of glacial acetic acid and aged for 14 an additional hour. The reaction mixture is then diluted with 25 ml. of 1:1 benzene-ether and extracted with 6 x 16 25 ml. of 3~ a~ueous sodium chloride. The solution is 17 then dried over sodium sulfate and evaporated in vacuo 18 to yield an oil. Recrystallization from ice-cold iso-9 propanol yives 5-fluoro-2-methyl-1-(p-methylsulfinyl benayl)-indene~
22 5-Fluoro-2-methyl~ p-methylthioben~yl)-indenylidene-23 3-acetic_ cid _ _ _ 24 To 41.8 g. (147 mmole) of the preceeding indene (from Example 12) is added 150 mi. of methanolic Triton B
~ .:
26 solution~ (53.2 g., dry basis; 317.5 mmole) and the batch, 27 under a nitrogen atmosphere, is brought to 35C. 14.63 G.
1 28 glyoxylic acid (198 mmole) is added and the batch, which ,~ 29 warms to 50-55C is aged one hour at 50C. It is then ~ 30 diluted with 250 ml~ of water and acidified with dilute :3 ! 22 .
,-. ,. . ~ . . .
.,~''P'~
sulfuric acid~ The product obtained in 90~ yield is re-2 crystallized to give the pure subjec~ product, melting 3 point 185.5-188C~ -4 When sodium hydroxide and tetramethylammonium chloride or tetramethylammonium hydroxide is used in . .
6 place of Triton B in the above example, the indenylidene- -, 7 3-acetic acid is obtained.
` 8 Similaxly, when 5-~luoro-2-methyl-1-(p-methyl-9 sulfinylbenzyl)indene is used in place of the corresponding ;- ~
10 methylthio compound in the above example, there is obtained Ll 5-~luoro-~-methyl-1-(p-methylsulfinylbenzyl)-ind~nylidene-12 3-acetic acid.
, ~ ~ 13 EXAMPLE 17 ,:.
14 5-Fluoro-2-methyl-1-(p-methylthiobenzylidene)-indene-3-15 acetic acid ___ _ __ 16 A suspension of 34.2 g. of 5-fluoro-2-methyl~
: i,i ~i 17 1-(p-methylthiobenzyl)-indenylidene -3-acetic acid (~rom ~; 18 Example 16) in 342 ml. o~ glacial acetic acid and 137 ml.
19 o concentrated ~Cl is stirred under a nitrogen atmosphere 20 at 90C for 10 hours. The reaction is cooled over 2 to , . , ' . , l 21 3 hours -to room temperature and aged an additional 3 hours .. . .
~,4'~,~ 22 at 20-25~. The batch is filtered, washed with 70:30 ~; , ,,:
23 acetic acid-water (ca. 100 ml.) then water-washed to remove ~ 24 excess acid. There is obtained 93% of product, melting ;`1 25 point 180-183C.
`~1 26 Similarly when 5-fluoro-2-methyl-1-(p-methylsul-!''.'~ 27 finylbenz~yl)-indenylidene~3-acetic acid is used in the .. .. .
28 above example in place of the corresponding methylthio 29 compound, there i5 obtained 5-fluoro-2-methyl-l~(p-methyl-,'s', ;3 t,;,,~
~`i` ;
, .j 1 sulfinylbenzylidene~-indene-3-acetic acid. The reaction 2 may be conductecl in an aprotic solvent such as 1,2-di-3 chloroethane under 100 p.~.i.g. of HCl gas at 50-100C.
5~Fluoxo-2-methyl-1-(p-methylsulfinylbenzylidene)-indene-6 _-acet c_acid _ __ _ 7 Seventeen grams (50 mmole) of the produc~ from 8 Example 17 is stirred in 94 ml. of chloroform and 40 ml.
9 of acetic acid under nitrogen and the temperature brought to 30C. To this slurry is added 5.3 ml. of 9.6N a~ueous 11 H2O2 (51 mmole) over one minute. The temperature is 12 brought to 35C. The batch is aged ~ total of 6 hours, 13 maintaining 35C internal temperature. After the age 14 period, 125 ml. of water is added and the C~CL3 layer con-centrated to a small volume in vacuo. The residue is 16 crystallized from 75 ml. of ethanol and the slurry cooled 17 to 0-5C and aged at 0-5C. The product is filtered and 18 washed with 15 ml. of cold (0-5C) 2BA ethanol and dried 19 in vacuo at 80C. The product weighs 16.3 g. (92%), . _ melting point 183-185C.
21 Similarly, when sodium periodate or potassium . '!
22 hypochlorite is used in place of hydro~en peroxide in , 23 the above example/ there is obtained the desired compound.
~ 4 EXAMPLE 19 :i:
`.t 25 2-Dimethylarninomethyl-4'-fluoropropiophenone ~, 26 A slurry of 14 g. (0.105 mole) of anhydrous 27 aluminum chloride in 14.4 g. (0.150 mole) of fluorobenzene '~ 28 and 24 ml. of carbon disulfide is cooled to 15C. To it 29 is added 0.100 mole of a-(dimethylaminomethyl)propionyl ;
bromide hydxobromide over 10-15 minutes at 15-20C. The ~, 31 reaction is stirred for five minutes at 20C and then 3 32 quenched on ice. The product is ext acted into chlorofo~n.
:i ~ 15576IA
: , 1 The chloroEorm layer is washed wi.h aqueous sodium bicar-2 bonate, dried over anhydrous sodium sulfate a~d concentrated 3 to give 2-bromo-4'-fluoro-2-methylpropiophenone.
:
; 4 EX~MPLE 20 5-Fluoro-2-methyl-1-(p-methylthiobenzyl)-inde~e 6 13 . 44 Grams ( O . 56 moleJ of magnesium turnings 7 are placed in a dried flask under N2 with 125 ml. of 8 ether and a crystal of iodine. Six ml. of 65 ml. solution 9 of 24.2 g. (0.14 mole) of p-methylthiobenzyl chloride in ether is added. After 3 to 5 minutes of stirring the 11 iodine color disappears and the reaction begins. ~fter 12 agil~g for 5 minutes, the rest of the benzyl chloride is 13 added dropwise over 45 minutes. It is rinsed in with 14 10 ml. of ether and the reaction aged for 2 hours with : l ~tirring. 21 Grams (0.128 mole) of 5-fluoro-2-methyl-1-.
16 indanone dissolved in 50 ml. of ether is added dropwise 17 over 30 minutes. After aging for 1 hour, the milky super-18 natent mixture is decanted from the magnesium into 100 ml.
19 of acetic acid. The flask and residual magnesium are rinsed into the acid solution with 4 x 50 ml. o~ benzene.
21 Two hundred ml. o water are added, the layers are 22 s-eparated and the organic layer is washed with 5 x 200 ml.
23 water. It is stripped to dryness after drying over 24 Na2SO4. The crude reaction product is crystallized from --hexane to give pure 5-fluoro-2-methyl-1-(p-methylthio-26 benzyl~-indene, melting point 58-59C.
28 5-Fluoro-2-methyl-1-(p-methylthiobenzylidene)-indene-3-29 acetic acid _ A suspension of 34 grams of 5-fluoro-2-methyl~
31 (p-methylthiobenzyl)-indenylidene-3 acetic acid in 150 ml.
32 of ethylene dichloride is heated to 70C in a glass .
,~ .
~ ~ 15576IA
1 lined autoclave. Anhydrous hydrogen chloride is admitted 2 until the preSsUre reaches 95 pound.-i~ The reaction is 3 stirred under these conditions for 10 hours and the excess 4 gas is then vented. The product slurried is cooled to 0-5C and after one hour is filtered and washed with 6 fresh ethylene dichloride. The yield product is 80~i.
.~,. .
. i :'`' ;.~'`
:. }
: . ~
..J
: .i .~ ~, .
i3 :.'.~ :
q , j ~! :
: ~ .
'';~ : -, 1 ~' .
.'~1~ .
.~ , ` .
.,I' :
.3 ;"`~
j~, ' ' ~
'. ~ '',' .'~ :
~,'1 ' '~' : ` '' "`~ ;.
;''''.' ~
!
: .l
Claims (16)
1. A process for preparing 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indene-3-acetic acid or its acid addition salt which comprises the steps of:
(a) condensing 5-fluoro-2-methyl-1-R1-benzyl-indene, wherein R1 is p-methylthio or p-methylsulfinyl with glyoxylic acid, its salt or ester, to form the corresponding 5-fluoro-2-methyl-1-(p-methylthio?or methyl-sulfinyl?benzyl)-indenylidene-3-acetic acid, salt or ester; and (b) isomerizing said indenylidene compound to form the desired indene -3-acetic acid com-pound when R1 is p-methylsulfinyl; when R1 is methylthio, isomerizing said indenylidene-3-acetic acid from Step (a) to form 5-fluoro-2-methyl-1-p-methylthiobenzylidene 3-indene acetic acid and subsequently oxidizing said 3-indene acetic acid or alternatively first oxidizing said 3-indenylidene acetic acid to form the corresponding 1-p-methylsulfinyl compound and subsequently isomerizing said 1-p-methylsulfinyl compound.
(a) condensing 5-fluoro-2-methyl-1-R1-benzyl-indene, wherein R1 is p-methylthio or p-methylsulfinyl with glyoxylic acid, its salt or ester, to form the corresponding 5-fluoro-2-methyl-1-(p-methylthio?or methyl-sulfinyl?benzyl)-indenylidene-3-acetic acid, salt or ester; and (b) isomerizing said indenylidene compound to form the desired indene -3-acetic acid com-pound when R1 is p-methylsulfinyl; when R1 is methylthio, isomerizing said indenylidene-3-acetic acid from Step (a) to form 5-fluoro-2-methyl-1-p-methylthiobenzylidene 3-indene acetic acid and subsequently oxidizing said 3-indene acetic acid or alternatively first oxidizing said 3-indenylidene acetic acid to form the corresponding 1-p-methylsulfinyl compound and subsequently isomerizing said 1-p-methylsulfinyl compound.
2. A process for preparing 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indene -3-acetic acid which comprises the steps of:
(a) condensing in the presence of a base 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene with glyoxylic acid, its salt or ester to form the corresponding 3-indenylidene acetic acid compound;
(b) isomerizing said 3-indenylidene acetic acid compound in the presence of a base or acid to form the 5-fluoro-2-methyl-1-(p-methylthio-benzylidene)-indene-3-acetic acid compound;
and (c) oxidizing said indene-3-acetic acid compound to the desired product.
(a) condensing in the presence of a base 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene with glyoxylic acid, its salt or ester to form the corresponding 3-indenylidene acetic acid compound;
(b) isomerizing said 3-indenylidene acetic acid compound in the presence of a base or acid to form the 5-fluoro-2-methyl-1-(p-methylthio-benzylidene)-indene-3-acetic acid compound;
and (c) oxidizing said indene-3-acetic acid compound to the desired product.
3. The process of Claim 2, wherein glyoxylic acid is used, and the isomerization is carried out in the presence of an acid.
4. A process for preparing 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indene-3-acetic acid or its acid addition salt which comprises the steps of:
(a) reacting 5-fluoro-2-methyl-1-indanone with an R1 benzyl compound wherein R1 is p-methylthio or p-methylsulfinyl under Grignard or Wittig conditions to form 5-fluoro-2-methyl-1-(R1-benzyl)-indene;
(b) condensing said indene compound with glyoxylic acid, its ester or salt to form 5-fluoro-2-methyl-1-R1-benzylindenylidene-3-acetic acid, ester or salt;
(c) when R1 is methylsulfinyl, isomerizing said indenylidene compound from Step (c) to form the desired product; or (d) when R1 is methylthio, isomerizing said indenylidene compound from Step (c) and subse-quently oxidizing to form the desired product;
or first oxidizing the product from Step (c) and subsequently isomerizing.
(a) reacting 5-fluoro-2-methyl-1-indanone with an R1 benzyl compound wherein R1 is p-methylthio or p-methylsulfinyl under Grignard or Wittig conditions to form 5-fluoro-2-methyl-1-(R1-benzyl)-indene;
(b) condensing said indene compound with glyoxylic acid, its ester or salt to form 5-fluoro-2-methyl-1-R1-benzylindenylidene-3-acetic acid, ester or salt;
(c) when R1 is methylsulfinyl, isomerizing said indenylidene compound from Step (c) to form the desired product; or (d) when R1 is methylthio, isomerizing said indenylidene compound from Step (c) and subse-quently oxidizing to form the desired product;
or first oxidizing the product from Step (c) and subsequently isomerizing.
5. The process of Claim 4, wherein R1 is p-methyl-thio and the reaction in Step (a) is carried out under Grignard conditions.
6. The process of Claim 5, wherein after Step (b) isomerization is first carried out.
7. A process for preparing 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indene-3-acetic acid or its salt which comprises the steps of:
(a) reacting a ketone of the formula:
wherein:
A is methyl or together with G forms methyli-dene;
B is hydrogen, methyl or halo;
G is methyl, CH2R or together with A forms methylidene, wherein R is halo, hydroxy, its ethers or esters or -N-(C1-5 alkyl)2; and (1) when A and G together is methyli-dene, B is methyl;
(2) when A and G are each methyl, B is halo; and (3) when A is methyl and B is hydrogen, G is CH2R;
under Friedel Crafts conditions to form 5-fluoro-2-methyl-1-indanone;
(b) reacting said 5-fluoro-2-methyl-1-indanone with an R1 benzyl compound wherein R1 is p-methylthio or p-methylsulfinyl under Grignard or Wittig conditions to form 5-fluoro-2-methyl-1-(R1-benzyl)-indene;
(c) condensing said indene compound with glyoxylic acid, its ester or salt to form 5-fluoro-2-methyl-1-R1-benzylindenylidene-3-acetic acid, ester or salt;
(d) when R1 is methylsulfinyl, isomerizing said indenylidene compound from Step (c) to form the desired product; or (e) when Rl is methylthio, isomerizing said indenyli-dene compound from Step (c) and subsequently oxidizing to form the desired product; or first oxidizing the product from Step (c) and subsequently isomerizing.
(a) reacting a ketone of the formula:
wherein:
A is methyl or together with G forms methyli-dene;
B is hydrogen, methyl or halo;
G is methyl, CH2R or together with A forms methylidene, wherein R is halo, hydroxy, its ethers or esters or -N-(C1-5 alkyl)2; and (1) when A and G together is methyli-dene, B is methyl;
(2) when A and G are each methyl, B is halo; and (3) when A is methyl and B is hydrogen, G is CH2R;
under Friedel Crafts conditions to form 5-fluoro-2-methyl-1-indanone;
(b) reacting said 5-fluoro-2-methyl-1-indanone with an R1 benzyl compound wherein R1 is p-methylthio or p-methylsulfinyl under Grignard or Wittig conditions to form 5-fluoro-2-methyl-1-(R1-benzyl)-indene;
(c) condensing said indene compound with glyoxylic acid, its ester or salt to form 5-fluoro-2-methyl-1-R1-benzylindenylidene-3-acetic acid, ester or salt;
(d) when R1 is methylsulfinyl, isomerizing said indenylidene compound from Step (c) to form the desired product; or (e) when Rl is methylthio, isomerizing said indenyli-dene compound from Step (c) and subsequently oxidizing to form the desired product; or first oxidizing the product from Step (c) and subsequently isomerizing.
8. The process of Claim 7, wherein the ketone of Step (a) is 4'-fluoro-2-halo-2-methylpropiophenone, and in Step (c) glyoxylic acid is used.
9. The process of Claim 7, wherein in Step (b) a p-methylthiobenzyl compound is used and after Step (c) isomer-ization is first carried out.
10. A process for preparing 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indene-3-acetic acid, or its salt, which comprises the steps of:
(a) reacting 4'-fluoro-2-halo-2-methylpropio-phenone under Friedel Crafts conditions to form 5-fluoro-2-methyl-1 indanone;
(b) reacting said 5-fluoro-2-methyl-1-indanone with a p-methylthiobenzyl compound under Grignard or Wittig conditions to form 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene;
(c) condensing said indene compound with glyoxylic acid in the presence of a base to form the corresponding 3-indenylidene acetic acid compound;
(d) isomerizing said 3-indenylidene acetic acid compound in the presence of a base or acid to form the 5-fluoro-2-methyl-1-(p-methylthio-benzylidene)-indene-3-acetic acid compound;
and (e) oxidizing said indene-3-acetic acid compound to the desired product or, if desired, first oxidizing the product from Step (c), followed by isomerization.
(a) reacting 4'-fluoro-2-halo-2-methylpropio-phenone under Friedel Crafts conditions to form 5-fluoro-2-methyl-1 indanone;
(b) reacting said 5-fluoro-2-methyl-1-indanone with a p-methylthiobenzyl compound under Grignard or Wittig conditions to form 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene;
(c) condensing said indene compound with glyoxylic acid in the presence of a base to form the corresponding 3-indenylidene acetic acid compound;
(d) isomerizing said 3-indenylidene acetic acid compound in the presence of a base or acid to form the 5-fluoro-2-methyl-1-(p-methylthio-benzylidene)-indene-3-acetic acid compound;
and (e) oxidizing said indene-3-acetic acid compound to the desired product or, if desired, first oxidizing the product from Step (c), followed by isomerization.
11. The process of Claim 10, wherein 4'-fluoro-2-bromo-2-methylpropiophenone is used, and the isomerization is carried out in the presence of an acid.
12. A process for preparing 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indene-3-acetic acid or its salt which comprises the steps of:
(a) reacting an acid halide of the formula:
wherein:
A is methyl or together with G forms methylidene;
B is hydrogen, methyl or halo;
G is methyl, CH2R or together with A forms methylidene, wherein R is halo, hydroxy, its ethers or esters or -N-(C1-5 alkyl)2;
Z is halo; and (1) when A and G together is methylidene, B
is methyl;
(2) when A and G are each methyl, B is halo;
and (3) when A is methyl and B is hydrogen, G
is CH2R;
with fluorobenzene under Friedel Crafts conditions to form 5-fluoro-2-methyl-1-indanone;
(b) reacting said 5-fluoro-2-methyl-1-indanone with an R1 benzyl compound wherein R1 is p-methylthio or p-methylsulfinyl under Grignard or Wittig conditions to form 5-fluoro-2-methyl-1-(R1-benzyl)-indene;
(c) condensing said indene compound with glyoxylic acid, its ester or salt to form 5-fluoro-2-methyl-1-R1-benzylindenylidene-3-acetic acid, ester or salt;
(d) when R1 is methylsulfinyl, isomerizing said indenylidene compound from Step (c) to form the desired product; or (e) when R1 is methylthio, isomerizing said indenylidene compound from Step (c) and subse-quently oxidizing to form the desired product;
or first oxidizing the product from Step (c) and subsequently isomerizing.
(a) reacting an acid halide of the formula:
wherein:
A is methyl or together with G forms methylidene;
B is hydrogen, methyl or halo;
G is methyl, CH2R or together with A forms methylidene, wherein R is halo, hydroxy, its ethers or esters or -N-(C1-5 alkyl)2;
Z is halo; and (1) when A and G together is methylidene, B
is methyl;
(2) when A and G are each methyl, B is halo;
and (3) when A is methyl and B is hydrogen, G
is CH2R;
with fluorobenzene under Friedel Crafts conditions to form 5-fluoro-2-methyl-1-indanone;
(b) reacting said 5-fluoro-2-methyl-1-indanone with an R1 benzyl compound wherein R1 is p-methylthio or p-methylsulfinyl under Grignard or Wittig conditions to form 5-fluoro-2-methyl-1-(R1-benzyl)-indene;
(c) condensing said indene compound with glyoxylic acid, its ester or salt to form 5-fluoro-2-methyl-1-R1-benzylindenylidene-3-acetic acid, ester or salt;
(d) when R1 is methylsulfinyl, isomerizing said indenylidene compound from Step (c) to form the desired product; or (e) when R1 is methylthio, isomerizing said indenylidene compound from Step (c) and subse-quently oxidizing to form the desired product;
or first oxidizing the product from Step (c) and subsequently isomerizing.
13. The process of Claim 12, wherein the acid halide is an .alpha.-haloisobutyryl halide, and R1 is a p-methylthio compound, and Step (c) is carried out under Grignard con-ditions.
14. The process of Claim 12, wherein in Step (c) glyoxylic acid is used, and after Step (c) isomerization is first carried out.
15. A process for preparing 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indene-3-acetic acid or its salt which comprises the steps of:
(a) reacting an .alpha.-haloisobutyryl halide under Friedel Crafts conditions with fluorobenzene to form 5-fluoro-2-methyl-1-indanone;
(b) reacting said 5-fluoro-2-methyl-1-indanone with a p-methylthiobenzyl compound under Grignard or Wittig conditions to form 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene;
(c) condensing said indene compound with glyoxylic acid in the presence of a base to form the corresponding 3-indenylidene acetic acid compound;
(d) isomerizing said 3-indenylidene acetic acid compound in the presence of a base or acid to form the 5-fluoro-2-methyl-1-(p-methylthio-benzylidene)-indene-3-acetic acid compound;
and (e) oxidizing said indene-3-acetic acid compound to the desired product or, if desired, first oxidizing the product from Step (c) followed by isomerization.
(a) reacting an .alpha.-haloisobutyryl halide under Friedel Crafts conditions with fluorobenzene to form 5-fluoro-2-methyl-1-indanone;
(b) reacting said 5-fluoro-2-methyl-1-indanone with a p-methylthiobenzyl compound under Grignard or Wittig conditions to form 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene;
(c) condensing said indene compound with glyoxylic acid in the presence of a base to form the corresponding 3-indenylidene acetic acid compound;
(d) isomerizing said 3-indenylidene acetic acid compound in the presence of a base or acid to form the 5-fluoro-2-methyl-1-(p-methylthio-benzylidene)-indene-3-acetic acid compound;
and (e) oxidizing said indene-3-acetic acid compound to the desired product or, if desired, first oxidizing the product from Step (c) followed by isomerization.
16. The process of Claim 15, wherein .alpha.-bromoiso-butyryl bromide acid is used, and the isomerization is carried out in the presence of an acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA296,336A CA1059528A (en) | 1973-12-20 | 1978-02-06 | Process for preparing 5-fluoro-2-methyl-1-indanone |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US426864A US3870753A (en) | 1973-12-20 | 1973-12-20 | Process for preparing indenyl acetic acids |
| US05/486,031 US3970693A (en) | 1974-07-05 | 1974-07-05 | Process for preparing indene acetic acids |
| US05/509,602 US3944600A (en) | 1973-12-20 | 1974-09-30 | Indenylidene-3-acetic acid process for preparing indene acetic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1044255A true CA1044255A (en) | 1978-12-12 |
Family
ID=27411527
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA215,636A Expired CA1044255A (en) | 1973-12-20 | 1974-12-10 | Process for preparing indene acetic acids |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS5331153B2 (en) |
| AR (2) | AR210484A1 (en) |
| CA (1) | CA1044255A (en) |
| CH (1) | CH616152A5 (en) |
| DD (1) | DD116819A5 (en) |
| DE (1) | DE2462380C2 (en) |
| DK (1) | DK140835B (en) |
| ES (2) | ES432921A1 (en) |
| FI (1) | FI62287C (en) |
| FR (1) | FR2255060B1 (en) |
| GB (1) | GB1479519A (en) |
| IE (1) | IE41529B1 (en) |
| NL (1) | NL170534C (en) |
| NO (2) | NO140857C (en) |
| SE (2) | SE426818B (en) |
| YU (2) | YU41017B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3732292A (en) * | 1970-05-01 | 1973-05-08 | Merck & Co Inc | Indenyl compounds |
| NL7200058A (en) * | 1971-01-21 | 1972-07-25 | ||
| US3822310A (en) * | 1971-01-21 | 1974-07-02 | Merck & Co Inc | Substituted indenyl acetic acids |
-
1974
- 1974-12-02 NL NLAANVRAGE7415701,A patent/NL170534C/en not_active IP Right Cessation
- 1974-12-02 SE SE7415063A patent/SE426818B/en not_active IP Right Cessation
- 1974-12-02 FI FI3489/74A patent/FI62287C/en active
- 1974-12-04 DK DK629674AA patent/DK140835B/en not_active IP Right Cessation
- 1974-12-05 NO NO744395A patent/NO140857C/en unknown
- 1974-12-10 CA CA215,636A patent/CA1044255A/en not_active Expired
- 1974-12-12 IE IE2557/74A patent/IE41529B1/en unknown
- 1974-12-13 ES ES432921A patent/ES432921A1/en not_active Expired
- 1974-12-13 YU YU3316/74A patent/YU41017B/en unknown
- 1974-12-14 DD DD183051A patent/DD116819A5/xx unknown
- 1974-12-16 GB GB54320/74A patent/GB1479519A/en not_active Expired
- 1974-12-17 FR FR7441519A patent/FR2255060B1/fr not_active Expired
- 1974-12-18 CH CH1682474A patent/CH616152A5/en not_active IP Right Cessation
- 1974-12-19 DE DE2462380A patent/DE2462380C2/en not_active Expired
- 1974-12-20 JP JP14580474A patent/JPS5331153B2/ja not_active Expired
-
1976
- 1976-01-30 AR AR262084A patent/AR210484A1/en active
- 1976-07-15 AR AR20633476D patent/AR206334A1/en active
-
1977
- 1977-01-25 ES ES455333A patent/ES455333A1/en not_active Expired
-
1979
- 1979-02-05 NO NO790360A patent/NO141892C/en unknown
-
1981
- 1981-03-05 YU YU00559/81A patent/YU55981A/en unknown
- 1981-12-22 SE SE8107702A patent/SE440774B/en not_active IP Right Cessation
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO1998033752A1 (en) | 2-substituted 7-haloindenes and methods for synthesizing | |
| US3562336A (en) | Synthesis of naphthalene derivatives | |
| JP3835846B2 (en) | Process for producing cyclopentadienyl compound and compound obtained | |
| US6465700B1 (en) | Coupling reactions of 2-substituted, 7-haloindenes with aryl substituents to produce metallocene catalyst ligands | |
| US3944600A (en) | Indenylidene-3-acetic acid process for preparing indene acetic acids | |
| US3970693A (en) | Process for preparing indene acetic acids | |
| CA1044255A (en) | Process for preparing indene acetic acids | |
| US3870753A (en) | Process for preparing indenyl acetic acids | |
| US3362988A (en) | Alkanoylnaphthyloxy-carboxylic acids | |
| US4078008A (en) | Process for the preparation of dienes | |
| CA1059528A (en) | Process for preparing 5-fluoro-2-methyl-1-indanone | |
| GB1599623A (en) | 2-(2,2-dihalovinyl)-thiophenes | |
| US3830862A (en) | Reactions involving carbon tetrahalides with sulfones | |
| JP2002517503A (en) | Synthesis of arylboric acid | |
| US3979471A (en) | Process for synthesizing ethylenic compounds | |
| US2872458A (en) | Addition product of a metal hydrocarbon mercaptide with an alpha-halogamma-butyrolactone | |
| JP4163763B2 (en) | Method for alkylating cyclopentadiene compounds | |
| EP0309626B1 (en) | Process for the preparation of dibenzothiepin derivative | |
| EP0220792B1 (en) | A method for producing 2-aryl-propionaldehydes | |
| US4933461A (en) | Preparation of a piperidinylcyclopentylheptenoic acid derivative | |
| KR900003281B1 (en) | Process for preparing derivatives of 2- thiophene acetic acid | |
| US2510732A (en) | Method of making 6-methyldihydrocodeine | |
| JPH0696564B2 (en) | α- (ω-hydroxyalkyl) furfuryl alcohol and process for producing the same | |
| US3703597A (en) | Preparation of benzilic acid compounds | |
| US3474150A (en) | Method for the production of 5-gamma-hydroxy - propylidene - substituted dibenzocycloheptenes |