WO2011113925A2 - Carbonylation of organic zinc compounds - Google Patents

Carbonylation of organic zinc compounds Download PDF

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WO2011113925A2
WO2011113925A2 PCT/EP2011/054104 EP2011054104W WO2011113925A2 WO 2011113925 A2 WO2011113925 A2 WO 2011113925A2 EP 2011054104 W EP2011054104 W EP 2011054104W WO 2011113925 A2 WO2011113925 A2 WO 2011113925A2
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ib
formula
compounds
licl
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Paul Knochel
Sebastian Bernhardt
Albrecht Metzger
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Ludwig-Maximilians-Universität München
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    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07C303/00Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
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    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D261/02Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07F3/00Compounds containing elements of Groups 2 or 12 of the Periodic System
    • C07F3/06Zinc compounds
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/32Addition reactions to C=C or C-C triple bonds
    • B01J2231/321Hydroformylation, metalformylation, carbonylation or hydroaminomethylation
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    • C07C2601/06Systems containing only non-condensed rings with a five-membered ring

Abstract

The invention relates to a method for producing organic compounds comprising at least one functional group, in particular carboxylic acids, alcohols, esters, amides, ketones, aldehydes or amines, and to compounds for the production thereof, to uses and to the production of such compounds.

Description

Carbonylation of organic zinc compounds

The invention relates to methods for the preparation of organic compounds having at least one functional group, in particular of carboxylic acids, alcohols, esters, amides, ketones, aldehydes, or amines, as well as compounds for their preparation as well as uses and the preparation of such compounds. State of the art:

The addition of organometallic compounds to carbonyl groups is of great interest, since such a direct access to eg alcohols, amines and carboxylic acids is possible. Organozinc compounds are characterized by their high tolerance to functional groups and would therefore ideal as a nucleophilic addition reaction of carbonyl groups are. Unlike magnesium compounds or organozinc zincate, however, are usually inert to the addition of carbonyl groups and provide only low yields. It is known that Lewis acids such as CeCl must be used 3 or LaCl 3 -2LiCl the reactivity of carbonyl to nucleophilic attack to increase (crater-sovskiy, 2006).

There is a basic need for new organometallic compounds and methods that direct the synthesis of organic alcohols, amines and carboxylic acids ER- possible.

A particular problem is the production of organic carboxylic acids. Organic carboxylic acids is of great economic importance, for example in the pharmaceutical field. Examples of economically important carboxylic acids are ibuprofen and phenylacetic acid derivatives (Martinez, 1993). The known synthetic routes are often complex and complicated or require toxic or expensive reagents.

The synthesis of ibuprofen is been carried out in the industry, among others, by the "Boot" method or the Hoechst process. The US 4,981,995 discloses a method using toxic carbon monoxide, and platinum. The US 5,068,448 discloses a method using corrosive hydrofluoric acid.

In the prior art various methods have been described to implement organometallic compounds with CO 2 to carboxylic acids. The pioneering work in the field of reactions of Organozinkreagenzien with CO 2 was done by Oshima (2008) and Dong (2008). However, these reactions were possible only in the presence of nickel or palladium-based catalyst systems. Kondo was able to show in 2009 that the implementation of Organozinkreagenzien with CO 2 in the absence of transition metal catalysts is possible. He used in his reactions zinc reagents that had been prepared by zinc insertion in the presence of LiCl. Due to the lower reactivity of these compounds he had to rely on the use of the toxic strongly polar solvent, DMF. In THF unsatisfactory results were achieved. Furthermore, the representation of the aromatic zinc reagents required the use of expensive aryl iodides. In addition, access to bisalkyl, Bisbenzyl- and bisaryl was not possible zinc reagents by the chosen Kondo display method. However, these are in terms of atom-economical and cost-based reaction is carried out is very important. The DE 10 2007 022 490.9 discloses Zinkamidbasen, form complexes with lithium chloride and magnesium chloride. Here, the zinc is bound in the complex to an amidic nitrogen atom. However, the implementation of Zinkamidbasen is possible only with electron-deficient aromatic and heterocyclic aromatic systems. Therefore, the zinc compounds have sufficient reactivity to CO 2. OBJECT OF THE INVENTION

The invention has for its object to provide methods and compounds which overcome the disadvantages mentioned above. The invention is in particular the object to provide an efficient process for the production of organic carboxylic acids. In this case, should be available in a simple manner and in an efficient process a wide variety of organic carboxylic acids. The process should be carried out preferably without toxic, aggressive or expensive reagents or catalysts. In particular, the use of precious metals should be avoided. The process should also be energy efficient feasible at low temperature and in a few steps in a short time.

The invention is in particular the problem of providing an efficient method for the synthesis of ibuprofen or similar organic carboxylic acids, which are of pharmaceutical schem interest.

The invention also has for its object to provide reagents that are suitable for the production of organic carboxylic acids. In addition to new efficient process for the preparation of organic compounds having at least one functional group, in particular of carboxylic acids, alcohols, esters, amides, Ke tone, aldehydes, or amines, and compounds are provided for their preparation.

Summary of the Invention

The object is surprisingly achieved by methods and compounds according to the claims.

The invention ren a process for the production of organic carboxylic comprising the steps of a) providing a compound of formula (Ia) or (Ib):

R-Zn-X MgX 2 LiCl, (Ia)

R ^ ^ Zn MgX LiCl, (Ib) where R, R 1 and R 2 are organic radicals and X is a halide,

Contacting with carbon dioxide and c) obtaining an organic carboxylic acid of formula (II):

R-COOH (II).

In a preferred embodiment of the invention, R, R 1 and R 2 are organic te RES, which are independently selected from benzyl radicals, aryl, heteroaryl and alkyl. In a compound (Ib) are preferably identical, R 1 and R 2, but they can also differ in a compound (Ib).

The halide, X is preferably I, Br or Cl. Preferably, the halide is Cl, and in particular is in the use of benzylic zinc reagents.

In the compounds of formulas (Ia) and (Ib), the zinc is bound to carbon atoms. Thus the compounds are organometallic nature. In one embodiment of the invention, the zinc in the compounds (Ia) and (Ib) not directly bonded to a heteroaryl radical.

In a preferred embodiment of the invention, R, R 1 and R 2 are benzyl, wherein the aromatic ring of the benzyl moiety is optionally substituted with at least one substituent R 4 which is selected as indicated below.

In a preferred embodiment of the invention at least one substituent R 4 is at the benzylic zinc reagent selected from alkyl, alkoxy, halogenated alkyl, Esteryl-, CN, -SMe, HNBoc, TMS (trimethylsilyl), OTIPS -NH 2, and -NR 5 2 where R 5 = H or alkyl. In the above-identified formulas, the length of the alkyl group is preferably from 1 to 10 carbon atoms, particularly preferably methyl, ethyl or propyl. The alkoxy group is preferably a methoxy or ethoxy. In a preferred embodiment of the invention, the compound of the formula in a step aO) first (Ia) or (Ib) is prepared starting from a compound of formula (III):

RX (III) preferably by reaction with magnesium, LiCl and ZnC .. the compound RX is a bromide, in particular an aryl bromide. These are cheaper and more readily available than the comparable iodides in general.

Compounds of formula (Ia) are known in the art. The preparation is in Piller et al. 2008, Metzger et al., 2008 described. The compounds of formula (Ib) have not been described in the prior art. They are obtained when you are in a process according to Piller et al. 2008, or Metzger et al, 2008 using a smaller amount of ZnCl 2, namely 0.5 equivalents based on the compound RX. The compounds of formula (Ia) and (Ib) are complex salt compounds. The respective formulas (Ia) and (Ib) represent substantially the stoichiometric composition of the complexes.

The zinc compounds employed in the present process are prepared by direct insertion of magnesium metal in organic halogen compounds in the presence of ZnCl 2 and LiCl (exemplified in Scheme 1). ZnCl 2

Figure imgf000007_0001

(0.5 equiv.)

R = aryl, benzyl, alk l

X = Cl, Br, I

Scheme 1: Example of organozinc compounds by direct Magnesiumin- sertion in the presence of ZnCl 2 and LiCl. R can also have other meanings, such as heteroaryl.

In a preferred embodiment, the preparation of the compounds (Ia) and (Ib) in a one-pot process is carried out. On an industrial scale pot processes are generally advantageous because complicated purification steps are eliminated and comparatively simple devices can be used. In a further preferred embodiment, the further conversion to organic acids or other organic compounds in the same one-pot process is carried out. It is according to the invention, however, also possible to intermediates, in particular the compounds (Ia) or (Ib), to isolate and store if necessary.

To ensure mild reaction conditions, it is advantageous that Magnesiumin- sertion in the presence of ZnCl perform second Characterized in that the Grignard reagent of the composition RMgX LiCl, which is apparent from the oxidative addition of the magnesium in the carbon-halogen bond, is waisted transmetalation by the pres- send ZnCl 2 immediately in situ to the corresponding most stable zinc compound is allowed. This procedure is in the preparation of aromatic, heteroaromatic and alkylic zinc reagents with sensitive functional groups (for example, esters or nitrile) as well as benzylic zinc reagents particularly preferred. Besides the very practicable Eintopiverfahren for the preparation of zinc compounds of type Ia and Ib it is also possible for organozinc compounds of the composition RZnX-LiCl with MgCl 2 powder or a solution of MgCl2 in THF to enable (Scheme 2, equation 1). The advantage of the one-pot method is here in the significantly shorter ren response times and low temperatures, which are necessary for the presentation and the ability to display diorganozincs. In addition, the representation of aromatic zinc compounds is possible by also be prepared in situ method of aryl bromides. Furthermore, it is also possible, Grignard compounds of the type RMgX-LiCl with Ζη0 2 - implement solution to compounds of type Ia and Ib (Scheme 2, equation 2). Compared to the one-pot process but there is here a limitation with respect to the functional groups, since it is assumed that an organomagnesium compound.

MgCl2

(1.0 equiv.)

RZnX-LiCl-RZnX MgCl 2 -LiCl (1)

R = aryl, benzyl, alkyl

X = Cl, Br, I

ZnCl 2

Figure imgf000008_0001

R = aryl, alkyl

X = Cl, Br, I Scheme 2: Further exemplary display possibilities of zinc compounds of the composition Ia and Ib. R can also have other meanings, such as hetero- aryl or benzyl.

This also emanating in one-pot process from the transmetallation MgCl2 coordinated in the form of complex aggregates of the composition RZnX-MgCl 2 -LiCl or R ^ Zn MgC ^ -LiCl in close proximity to the zinc atom. This coordination sphere then enables probably stands on six-membered transition state, under Lewis acid activation, the addition of C0 2 (Scheme 2a), carbonyl compounds and imines.

Cl

Figure imgf000009_0001

Scheme 2a: Lewis acid mediated addition of Organozinkreagenzien of CO 2.

Compounds of formula (Ia) and (Ib) can be prepared directly with C0 2 to implement the corresponding carboxylic acids 3 (Scheme 3).

C0 2 (1 bar)

-MgCl 2 R ZnX LiCl R-COOH

25 to 50 ° C, 48 h

3

C0 2 (1 bar)

R 2 Zn-2 2MgX -2LiCI 2 R-COOH

25 to 50 ° C, 48 h

3

R = aryl, benzyl, alkyl

X = Cl, Br, I Scheme 3: Exemplary addition of organozinc compounds to CO 2 - Preparation of carboxylic acids. R can also have other meanings such as heteroaromatics ryl.

The invention also provides a compound of formula (Ib):

RR 2 -Zn MgX 2 LiCl, (Ib) wherein R 1 and R 2 are organic radicals and X is a halide. Incidentally, (Ib), the radicals R 1 in the formula, R 2 and X are preferably selected as indicated above.

The invention also provides a process for preparing a compound of formula (Ib), wherein a compound of formula (III):

RX (III)

is reacted in a reaction with magnesium, LiCl and ZnX 2 to the compound (Ib), wherein R is an organic radical and is preferably selected as stated above. The halides of RX and ZnX 2 may be the same or different selected. The reaction of a compound R-X with magnesium is exemplarily shown in Scheme 4, where the radicals FG are reproduced for example.

Mg (2.5 equiv.),

(FG) -RX ► 0.5 (FG) -R-Zn-R (FG) -2MgX 2 -2LiCI

ZnCl 2 (0:55 equiv.),

LiCl (1.5 equiv.),

THF.T, t

R = benzyl, aryl, heteroaryl, alkyl,

X = Cl, Br, I

FG = OMe, CF 3, Hai, C0 2 Et, CN, SMe, HNBoc, TMS, NR 2, OTIPS

Scheme 4: Preparation of diorganozinc by direct Magnesiuminserti- one in the presence of ZnCl 2 and LiCl. It has been found that the diorganozinc (Ib) in general have an excellent reactivity with C0. 2 In comparative experiments it was found that the reactivity is higher than with the comparable Monoorganozinkverbindungen (Ia). Therefore, when using the compounds of formula (Ib), a particularly economical see reaction is possible. For example, two R's may be the most quantitatively converted to carboxylic acids per zinc atom. In the case of the mono benzylic zinc reagent only one residue can be converted to the corresponding carboxylic acid per zinc atom.

The compounds of formula (Ib) exhibit good stability. The organozinc species were generally prepared in 20 mmol scale and then within a period of 2 - consumes 3 weeks. During this period, no significant change in concentration could be determined by titration to iodine.

The compounds of formula (Ib) according to the invention can generally be used for the preparation of organic compounds having functional groups such as carboxylic acids, esters, ketones, imides, alcohols, amides or amines, for example using carbon dioxide, carbonyl compounds, isocyanates or imines. Here, for example ketones or aldehydes can be used for the production of alcohols as starting materials. The reaction with imines allows the preparation of amines. The reaction with isocyanates allows the display of amides. The further esterification or amidation of products allows the synthesis of esters and amides. As raw materials a compound RX as described above. The conduct of proceedings can take place in analogy to the procedures of butchers, 2008, Piller, of 2008. In addition, reactions with other starting compounds, such as nitrites, epoxides, thioesters, etc. are conceivable.

In a preferred embodiment of the invention, the compound (Ia) l- (4'-isobutyl-phenyl) ethyl-Zn-Cl-MgCl 2 -LiCl and the compound (II) ibuprofen. Ibuprofen is an important medicine that among other anti-inflammatory (anti-inflammatory), analgesic (analgesic) and antipyretic (antipyretic) acts. comparable synthesis ziehtet entirely on the use of toxic and expensive reagents and used no ecologically highly questionable transition metal based catalyst systems such as palladium catalysts. Thus providing these Ibupro- newly developed fensynthese more cost-effective and environmentally unbedenklicheren access to ibuprofen (8) in very high yield (Scheme 5).

Figure imgf000012_0001

6: 94%

Scale) ), .)

Total yield (over 4 steps): 59%

Figure imgf000012_0002

8: 7 89%: 70%

(1.8 mmol scale) (10 mmol scale)

Scheme 5: New synthesis of ibuprofen (8).

The synthesis of ibuprofen goes from commercially available 4-isobutylacetophenone

(4), which is reduced with NaBH 4 to the corresponding benzylic alcohol. 5 After reaction of the alcohol 5 with thionyl chloride the corresponding secondary benzylic 6 is obtained in 94% yield over two steps. The reaction with magnesium in the presence of ZnCl 2 and LiCl delivers at 25 ° C after 2 h the appropriate zinc reagent 7 in 70% yield. The direct reaction with CO 2 at normal pressure provides for a very simple work-up step ibuprofen in 89% yield.

In a preferred embodiment of the invention comparison to the invention is used to drive the preparation of phenylacetic acid derivatives. The starting compound of formula (III) then connect aryl / heteroaryl-CH 2 -X or a derivative thereof is used. The reaction of the benzylic zinc compounds of the formula (Ia) or (Ib) with C0 2 enables the preparation of phenylacetic acid derivatives of the type 9, which are common targets of pharmaceutical chemistry.

Figure imgf000013_0001

Scheme 6: Exemplary general representation of phenylacetic acid derivatives of the type. 9

As stated above and shown in the embodiments of the inventive method for production of a variety of organic acids can be used. In preferred embodiments of the invention, the method for the production of ibuprofen, naproxen, Fluribiprofen, carprofen, phenylacetic acid or derivatives of these acids is used.

The method of the present invention, registration with the used zinc reagents differs markedly 2 Zn-2MgCl emerge 2 -2LiCl of organozinc species consisting of metallation reactions with the zinc amide (tmp). Since it midbase is using the Zinka- only possible electron-deficient aromatic or heteroaromatic systems to metalate, in this way, even aromatic zinc reagents with strong electron-withdrawing functional groups or very electron-deficient heterocyclic zinc reagent can be obtained. However, these zinc species are not reactive enough to react with the electrophile CO 2 due to their electronic properties. Consequently, even with these substrate classes Metallierungsmethodik is not an alternative to those used here oxidative addition to the presentation of the zinc reagents.

EXAMPLES

Representation of different carboxylic acids, 4-methoxy-benzoic acid (Table 2, Example 9)

Figure imgf000014_0001

A Schlenk tube was annealed in a high vacuum and over calcium chloride predried CC "2 gas filled. Bis (4-methoxyphenyl) zinc-magnesium chloride lithium chloride (12.8 ml, 00:39 M in THF, 5.0 mmol) was added and C0 2 gas for 5 min passed through the solution. the reaction mixture was stirred for 6 h at 25 ° C. It was (50 ml) was added diethyl ether and the organic phase extracted with 2 M NaOH (3 x 50 ml). the combined aqueous phases were washed with 2 M HCl and extracted with diethyl ether (3 x 50 mL) (<5 pH). the combined organic phases were dried over sodium sulfate and the solvent removed in vacuo. 4-methoxy benzoic acid (1.47g, 9.6 mmol, 96%) was obtained as colorless finely crystalline solid conservation th. The reaction is represented as an entry 9 in Table 1.

Were synthesized in accordance with the above embodiment, carboxylic acids according to the method with CO2. In Table 1, the reactions are shown. the reaction times and yields are given in each case.

Table 1: Reaction of Organozinkverbmdungen with CO 2 to carboxylic acids.

yield

Entry zinc reagent time (h) Product

(%)

Figure imgf000015_0001

ΜθΟ ^ MeO OH

"Zn-2MgCI 2 -2LiCI

25/22 ° 100 CYO

24 h (12 h /

Figure imgf000015_0002

50 ° C)

Figure imgf000015_0003

OH

"Zn-2MgCI 2 -2LiCI

2/25 100 ° CYO

MeO 'MeO-kZn 2MgBrCI 2LiCI-12/50 ° C 76 C0 2 H

MeO- Zn 2MgCI 2 -2LiCI 3/25 ° C MeO /> - C0 2 H 96

Figure imgf000015_0004
In the use of benzylic Zmkreagenzien there is no limitation with respect to the electronic properties of the functional groups or substituents on the aromatic ring. Here (entry 4) is shown both in the presence of electron-withdrawing (entry 3) as well as electron-donating functional groups, a comparable high reactivity to CO 2. The utility alkylic zinc reagents was shown the example of the display of heptanoic acid (entry 8). In the case of the aromatic zinc reagents electron donating groups can be observed a good reactivity to CO 2 (entries 9 - 10) only in the presence. In the presence of electron-withdrawing groups, a lower reactivity to CO 2 shows.

In comparison to the known reactions of organozinc species with CO 2, the innovation and advantage of the invention on the one hand is that the reactions can be carried out in the toxicologically acceptable solvent THF under relatively mild conditions without transition metal catalysis. Furthermore it could be shown that functionalized benzylic zinc reagent composition RZnCI LiCl (R: benzyl), which had been prepared by zinc insertion in the presence of LiCl showed no reactivity to CO 2 in THF.

Synthesis of Ibuprofen

A: Preparation of l- (l-Chloro-ethyl) -4-isobutyl-benzene (6)

Figure imgf000016_0001
Sodium borohydride (1.71 g, 45.0 mmol) was added portionwise to a solution of 4-isobutylacetophenone (4, 5.28 g, 30.0 mmol) in methanol (75 ml). The reaction mixture was boiled for 1 h under reflux, cooled to room temperature and then washed with 1 M HCl (50 ml) was added. The solvent was distilled off and the resulting aqueous phase with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated sodium chloride solution (3 x 50 ml) and then dried over sodium sulfate. The solvent was removed in vacuo. The reduction of 4-isobutylacetophenone (4) was based on: A. A Ramini, MC Cesta, S. Coniglio, C. Bimani, S. Colagioia, V. D'Elia, M. Allegretti J. Org. Chem. 2003, 68, 7911th

The obtained crude product 5 was dissolved in dry dichloromethane (30 ml) and added dropwise with ice bath cooling with a solution of thionyl chloride (3:57 g, 30.0 mmol) (8 ml) in dichloromethane. The reaction mixture was slowly warmed to room temperature and then stirred for 12 h. The mixture was carefully treated with saturated sodium bicarbonate solution (40 mL) and then with dichloromethane (3 x 40 mL) the aqueous phase. The combined organic phases were dried over sodium sulfate and the solvent is then removed in vacuo. l- (l-Chloro-ethyl) -4-isobutyl-benzene (6) was obtained as a pale yellow liquid (5.55 g, 28.2 mmol, 94%).

B: Preparation of l- (4'-isobutyl-phenyl) ethylzinkchlorid- magnesium chloride lithium chloride (7)

Figure imgf000017_0001

LiCl (1:06 g, 25.0 mmol) was dried in a Schlenk tube for 10 min at 500 ° C in a high vacuum and then dissolved in THF (lO ml) under argon. ZnCl 2 (11.0 ml, 11.0 mmol, 1:00 M in THF) and magnesium turnings (0.61 g, 25.0 mmol) was added and the reaction mixture cooled with a water bath to 25 ° C. l- (l-Chloro-ethyl) -4-isobutyl-benzene (6, 1.97 g, 10.0 mmol) was added dropwise and the reaction mixture stirred for 2 h at room temperature. Titration of the zinc reagent 7 to iodine concentration gave a 0.33 M (7.2 mmol, 72%).

C: Preparation of Ibuprofen (8)

Figure imgf000018_0001

A Schlenk tube was annealed in a high vacuum and filled with pre-dried over calcium chloride C0 2 gas. l- (4'-isobutyl-phenyl) ethylzinc chloride-magnesium chloride lithium chloride (7, 5.6 mL, 0:32 M in THF, 1.8 mmol) was added and directed C0 2 gas for 5 minutes through the solution. The reaction mixture was for 12 hours at 25 ° C. and then heated to 50 ° C for 12 h. Was added diethyl ether (20 ml) and the organic phase washed with 2 M NaOH (3 x 20 mL). The combined aqueous phases were acidified with 2 M HCl (pH <5) and extracted with diethyl ether (3 x 20 ml). The combined organic phases were dried over sodium sulfate and the solvent removed in vacuo. Ibuprofen (8, 332 mg, 1.61 mmol, 89%) was obtained as a pale yellow fine crystalline solid. Comparison of the reactivity of mono and bisbenzylic zinc compounds

The reaction according to the invention with the electrophile C0 2 was prepared starting from mono benzylic zinc reagent composition RZnCl-MgCl 2 -LiCl (prepared according to Metzger, 2008) and bisbenzylic zinc reagents in a comparative experiment carried ü hrt. S okonntebeider U msetzungvon 4-fluoro benzylzinkchlorid-magnesium chloride lithium chloride with CO 2 after 12 h at 50 ° C (4-fluoro-phenyl) -acetic acid (2) in 61% yield to be isolated (see Scheme 7 below). When using bis (2-fluoro-benzylzink) -Magnesiumchlorid-lithium chloride (3) (2-Fluoro-phenyl) -acetic acid was isolated (4) after 6 h at room temperature in 100% yield.

C0 2 (1 bar)

ZnCl MgCl LiCl C0 2 H

THF, 12 h, 50 ° C

2: 61%

Figure imgf000019_0001

4: 100%

Scheme 7: Comparative analysis of the reactivity of the benzylic zinc reagent composition RZnCl-MgCl 2 -LiCl and R 2 Zn-2 2MgCl -2LiCl.

The comparative experiment demonstrates that bisbenzylic zinc reagents of the present invention the composition R 2 Zn-2 2MgCl -2LiCl a higher reactivity toward C0 2 having as the primary benzylic zinc reagent composition RZnCl-MgCl 2 -LiCl.

The results shown in the exemplary embodiments show that in total, it is possible to implement organozinc or diorganozinc by direct reaction with CO 2 extremely simple to the corresponding carboxylic acids. This can be an easy, cost-effective and ecologically safe synthesis of organic carboxylic compounds such as ibuprofen realize. This synthesis is compared to the previously known display options is a significant improvement, as can be dispensed with the use of toxic and expensive transition metals and others.

Preparation of alcohols and amines addition to the high reactivity of Organozinkreagenzien of the type Ia and Ib compared with C0 2 was observed high reactivity of the compounds of type Ib with aldehydes and ketones. In order to illustrate the influence of the MgCl 2 was fol- constricting comparative experiment carried out (Scheme 8):

Figure imgf000020_0001

Scheme 8: Preparation of an alcohol, the presence of MgCl 2 (. 1.0 equiv) is responsible for these dramatic speed acceleration. Diorganozinc are much more reactive than or- ganozinkhalogene and thus these compounds are also suitable for addition reactions to ketones. ? The reaction of i ZS (4-methoxyphenyl) zinc (5a) which, starting from 4-bromoanisole ( "BuLi, -78 ° C, 2 h; then ZnCl 2 (0.5 equiv.)) Was prepared, to 4- isobutylacetophenone (2b) does not expire (25 ° C, 12 h). The Diarylzinkreagenz 6a was prepared by reaction of 4-bromoanisole (1.0 eq.) With Mg (2.5 eq.), LiCl (0.75 eq.) And ZnCl 2 (0:55 eq.) In THF at 25 ° C within 2 h. However, the corresponding Diarylzinkreagenz 6a which MgX 2 (. X: Cl, Br; 2.0 equiv) responding includes the ketones 2b within 2 h at 25 ° C and both Ar groups are on the ketone transferred (equation 2, Scheme 8 ).

Were carried out further reactions, which are schematically illustrated in Table 2 below. Table 2: Further reactions of organozinc compounds. [A] Complexed LiCl has been omitted for reasons of clarity, [b] To the extent not shown otherwise, all reactions at 25 ° C Isolated yield of analytically pure product, [d] X = Cl, Br were carried out, [c]. [E ] reaction performed at 50.degree.

Figure imgf000021_0001

Figure imgf000022_0001

There are bisarylische zinc compounds of type 6; used (Ar 2 Zn-2 2MgX -2LiCl 0.6 equiv.). In these cases, both Ar groups are transmitted during the Carbonyladditions- reaction. The addition of i? Z 's- (4-methoxyphenyl) zinc 2MgX 2 -LiCl (6a) to aliphatic ketones such as dicyclopropylketone (2h) or cyclopentanone (2i) run within 2 h and 12 h, and lead to the alcohols 3h-i in 84-87% yield (entries 2-3). The use of 4-MeO (C 6 H 4) ZnBr-MgCl2 -LiCl (1.2 eq.) Instead Bisarylzinkreagenz 6a (0.6 equiv.) Results in 30% conversion of the ketone 2 h under the same reaction conditions. 5z5- (2-trifluoromethylphenyl) zinc 2MgX 2 -LiCl (6b) is reacted with the heterocyclic aldehyde to the corresponding 2j 3j pyridyl alcohol in 82% yield (entry 4). The electron-rich Arylzinkreagenz 5z5- (4-trimethylsilylphenyl) zinc 2MgX 2 -LiCl (6c) is added to 4-cyanobenzaldehyde (2g) in almost quantitative yield and provides benzhydryl alcohol 3k (entry 5). Likewise 5z '5- (4-N, N-dimethylaminophenyl) zinc reacts 2MgX 2 -LiCl (6d) with ketone 2 h in 24 hours and leads to the desired product 31 (74%; entry 6). i? z '[6e and i s- (5-pyrazolyl) zinc 2MgX 2 -LiCl? z' s- (l, 2-oxazol-4-yl) zinc 2MgX 2 -LiCl 6f add to substituted benzaldehydes (2k -l) and deliver the heterocyclic secondary alcohols (3m-n) in 83-91% yield (entries 7-8). Instead of using Benzylzinkchloriden type 8 (ArCFLZnCl-MgC ^ -LiCl;. 1.2 equiv)?, It is also possible i z 'sbenzylzinkverbindungen type 9 ((Ar 2) 2 Zn-2 2MgCl -LiCl;. 0.6 equiv) to use. Both benzylic groups are transferred to the electrophile. The presence of MgCl2 allows direct addition of organozinc compounds to N-tosyl imines. The reaction of Benzylzinkchlo- rid 9a N-Tosylimin 2r afford the expected product 3u within 24 h at 25 ° C in 86% yield (entry 10).

Literature: A. Krasovskiy, F. Kopp, P. Knöchel, Angew. Chem. Int. Ed. 2006, 45, 497-500.

FM Piller, P. Appukkuttan, A. Gavryushin, M. Helm, P. Knöchel, Angew. Chem. Int. Ed. 2008, 47, 6802; b) A. Metzger, F. Piller, P. Knöchel, Chem Comm 2008 5824th

A. Metzger, F. Piller, P. Knöchel, Chem. Commun., 2008, 5824

H. Ochiai, M. Jang, K. Hirano, H. Yorimitsu, K. Oshima, Org. Lett. 2008, 10, 2681. CS Yeung, VM Dong, J. Am. Chem. Soc. 2008, 130, 7826th

K. Kobayashi, Y. Kondo, Org. Lett. 2009, 11, 2035th

A. Krasovskiy, V. Malakhov, A. Gavryushin, P. Knöchel, Angew. Chem. Int. Ed. 2006, 45, 6040th

Claims

claims
1. A process for the production of organic carboxylic acids comprising the steps of a) providing a compound of formula (Ia) or (Ib):
R-Zn-X MgX 2 LiCl, (Ia)
R ^ Zn ^ ^ MgX LiCl, (Ib) where R, R 1 and R 2 are organic radicals and X is a halide, b) brought into contact with carbon dioxide and c) obtaining an organic carboxylic acid of formula (II):
R-COOH (II).
2. The method of claim 1, wherein R, R 1 and R 2 are organic radicals which are independently selected from benzyl, aryl, heteroaryl and alkyl groups.
3. The method according to at least one of the preceding claims, wherein R, R 1 and / or R 2 are benzyl, where the aromatic ring is optionally substituted with at least one substituent R 4.
4. The method of claim 3, wherein the at least one substituent R 4 is selected from alkyl, alkoxy, halogenated alkyl, Esteryl-, CN, -SMe, HNBoc, TMS, OTIPS -NH 2, and -NR 5 2 with R 5 = H or alkyl.
5. The method according to at least one of the preceding claims, wherein in step aO) first the compound of formula (Ia) or (Ib) is prepared, Starting from a compound of formula (III):
RX (III) by reaction with magnesium, LiCl and ZnCl. 2
6. The method according to at least one of the preceding claims, wherein the compound (Ia) l- (4'-isobutyl-phenyl) ethyl-Zn-Cl-MgCl 2 -LiCl, and the compound (II) is ibuprofen.
thereof 7. A method according to any one of the preceding claims for the production of ibuprofen, naproxen, Fluribiprofen, carprofen, phenylacetic acid or derivatives thereof.
8. A compound of formula (Ib):
R 1 R 2 2 Zn-2MgX -2LiCl, (Ib) wherein R 1 and R 2 are organic radicals and X is a halide.
9. A compound according to claim 8, wherein R 1 and R 2 are organic radicals which are independently selected from benzyl, aryl, heteroaryl and alkyl groups.
10. A compound according to any one of claims 8 or 9, wherein R 1 and / or R 2 are benzyl, where the aromatic ring is optionally substituted with at least one substituent R 4.
11. A compound according to claim 10, wherein the at least one substituent R 4 is selected from alkyl, Alkyoxy-, halogenated alkyl, Esteryl-, CN, -SMe, HNBoc, TMS, OTIPS -NH 2, and -NR 5 2 with R 5 = H or alkyl.
12. A process for preparing a compound of formula (Ib) according to any one of claims 8 to 11, wherein a compound of formula (III):
RX (III) with magnesium, LiCl and ZnX 2 to the compound (Ib) is reacted, in which R is an organic radical.
13. The use of compounds of formula (Ib) according to any one of claims 8 to 11 for the preparation of organic compounds having at least one functional group, in particular of carboxylic acids, alcohols, esters, amides, ketones, aldehydes, or amines, in particular by reaction with carbon dioxide , carbonyl compounds, imines or isocyanates.
14. The use of compounds of formula (Ia) according to any one of claims 1 to 7 for the preparation of carboxylic acids by reaction with carbon dioxide.
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EP2746259A1 (en) 2012-12-21 2014-06-25 Basf Se Substituted [1,2,4]triazole and imidazole compounds
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CN106518655A (en) * 2016-09-08 2017-03-22 山东理工大学 Method for preparing flaky ibuprofen crystal by adding crystal-growing controlling agent into aqueous solution

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