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Chapter 8

Downloaded by PENNSYLVANIA STATE UNIV on July 19, 2012 | http://pubs.acs.org Publication Date: November 25, 2003 | doi: 10.1021/bk-2004-0870.ch008

Dihydro-7-benzofurancarboxylic Acid: An Intermediate in the Synthesis of the Enterokinetic Agent Rl08512 1

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Bert Willemsens , Alex Copmans , Dirk Beerens , Stef Leurs , Dirk de Smaele , Max Rey , and Silke Farkas 1

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1

Chemical Process Research Department, Janssen Pharmaceutica, Turnhoutse weg 30, 2340 Beerse, Belgium Chemical Process Research Department, Cilag Ltd., Hochstrasse 201/209, 8201 Schaffausen, Switzerland

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A facile and scalable method for the synthesis of 4amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid, an intermediate in the synthesis of the enterokinetic agent R108512, has been developed. The key step in the synthesis is a zinc mediated ring closure of methyl 4-(acetylamino)-3bromo-2-(2-bromoethoxy)-5-chlorobenzoate. The ring closure can be achieved without preliminary activation of the zinc on condition that the oxygen content in the reaction mixture is lower than 0.5%. The new process eliminates hazardous chemicals (ethyleneoxide) and low temperature reactions (70°C, n-BuLi)

© 2004 American Chemical Society In Chemical Process Research; Abdel-Magid, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.

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Introduction Constipation is the most common gastrointestinal complaint, with more than two million patient visits in the United States per year, and probably an even larger number of individuals trying to remedy the symptom by selfmedication. [7] Slow transit constipation, a particular form of constipation for which no clear underlying cause has been defined, is characterized by a lack of massive bowel movements in the large intestine. This type of movement is responsible for the transport of the colonic content along the large bowel. In essence, slow transit constipation can be regarded as a result of a motor dysfunction, i.e. a lack of prokinetic activitity in the large intestine. It is well documented that stimulation of serotonin 5-HT receptors in the gut increases the motility throughout the gastrointestinal tract.[2,5] Therefore it is believed that gastrointestinal prokinetic agents have an important role to play in the treatment of slow transit constipation. Prucalopride,[4] a highly potent and selective serotonin 5-HT agonist, clearly demonstrates efficacy in clinical studies.[5-i0] Prucalopride is isolated either as the hydrochloric acid salt R093877 or as the succinate R108512 (Figure 1). 4

4

• HC1

R093877

• CH -COOH I CH -COOH

R108512

2

2

Figure 1. Rl08512 An important intermediate in the synthesis of prucalopride is 4-amino-5chloro-2,3-dihydro-7-benzofurancarboxylic acid 1, which after coupling with 1(3-methoxypropyl)-4-piperidinamine 2, gives the anilide 3 yielding R093877 or R108512 after salt formation (Scheme 1).

In Chemical Process Research; Abdel-Magid, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.


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3

Scheme 1. Penultimates The medicinal chemistry route to prepare the anilide 3 , as outlined in Scheme 2, follows the procedure of Marburg and Tolman.[7i] Though this route was applied to prepare the early toxicology and clinical batches, the use of ethylene oxide, benzene, JV-chloro- and iV-bromosuccinimide together with the low temperatures required for the w-BuLi reactions prevented the introduction of this method into our chemical production plant. Besides these inconveniences, chlorination of 4-amino-2,3dihydrobenzofuran 4 to the 5-ehloro derivative 5 is not regioselective and a chromatographic purification was necessary to remove the 7-chloro isomer 6.

Scheme 2. Medicinal Chemistry route


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Alternative Routes In 1993 Bedeschi et al.[72] published the synthesis of the dihydrobenzofurancarboxylic acid 1 using a palladium catalysed coupling of trimethylsilylacetylene with methyl 4-(acetylamino)-3-iodo-2-hydroxy-5chlorobenzoate. Most of the alternatives we investigated were performed prior to this publication and moreover trimethylsilylacetylene is not a reagent of choice to introduce in a production plant due to it's high price and low atom efficiency. Several alternatives to the synthesis of 1 have been investigated and besides the final method, two of them merit consideration in some detail. A three step route to compound 5 is possible via the application of Marburg and Tolman's method to the commercially available 2-chloro-5-methoxyaniline 7 as outlined in Scheme 3. Starting with this aniline eliminates the regioselectivity problems encountered during the chlorination. Ring closure of the hydroxyethylated compound 8 however resulted in the formation of the dihydroindole 9 rather than the desired dihydrofuran 5.

9

Scheme 3: Attempted preparation of 5 from 2 chloro-5-methoxy aniline Another approach to the synthesis of the dihydrobenzofurancarboxylic acid 1 is outlined in Scheme 4. The key reaction in this alternative is the HoubenHoesch reaction on methyl-4-amino-2-methoxy-5-chloro benzoate 10. HoubenHoesch reaction on anilines, giving exclusively ortho amino ketones has been described by Sugasawa.[i5] Under these reaction conditions, the ether function is demethylated to provide the keto-phenol 11. Compound 11 can then be cyclized under very mild conditions to the furanone 12 which, after reduction



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and subsequent dehydration gives the benzo&ran derivative 13. Hydrogenation of this benzofliran to the dihydrobenzofuran 14 was accomplished with rhodium as catalyst. Though the reduction proceeded quantitatively, the isolated 14 contained about 4% of dechlorinated product. As earlier investigations indicated, this impurity most probably could be reduced to an acceptable level leading to a scalable method in our pilot plant. For the final production method however the use of borontrichloride would create significant amounts of boroncontaining waste and had to be eliminated. Therefore, in parallel to the HoubenHoesch approach another alternative was investigated. 1) C1CHCN 2

2.1 eq

Scheme 4: Houben-Hoesch approach

Commercial Process The method finally introduced in production is outlined in Scheme 5. In the following section the development will be described in more detail.


130 HO

Br

2

CH OOCM\

/>—NH—C—CH

3

3

CI

( 1

.

HQ -

l e q )

= —ui uuun\ 16h-22°C (98%) 3

15

Br a CI

16

Br /

1) BrCH CH Br (2 eq) 2

B t

DMA 2 3

K


y—

2

°\j /===\

CQ

2) Crystallisation toluene (62%)

CH OOC-6 3

1

9

>NH-C-CH

3

)

Z

n

0-05ecD DMA

2) HC1 aq.

17

(60%)

Scheme 5: Commercial process

Bromination Step Bromination of the commercially available salicylic acid derivative 15 was first attempted in pure acetic acid and two equivalents of bromine to obtain an acceptable conversion. As shown in Table 1, lower excess of bromine and longer reaction times or elevated temperatures lead to the formation of the deacetylated product as an impurity. When switching to an aqueous solvent system much better conversions were obtained and the amount of bromine could be reduced to 1.1 equivalent. As illustrated in Table 2, bromination in aqueous acetic acid gave almost complete conversion and the product could be filtered directly from the reaction mixture. Bromination in water gave incomplete conversion.


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Table I: Bromination in anhydrous acetic acid Results after 16 and 20 hours are on isolated compound, other results are in process controls. eq. Br

2

Temp. °C


2

Time

LCwt% Product starting Deacetylated material product. 2 94

20-30

16h

20-45

3h

98

1.5

1.8

20-45

3h

93

3

1.5

20-45

lh

89

8

16h

69

2

5h

82

14

20 h

87

8

2h

76

2

1.25

20-30

1.25

40-80

21

20

Table II: Bromination in aqueous solvent systems Results after 16 hours at 22-26°C. Solvent H0 2

H 0 / CH3COOH (1/1) 2

LC wt% (isolated product) product starting material 96.5 3.3 99.3

0.03

Yield 71% 98%

Bromoethylation In screening experiments bromoethylation of phenolic derivative 16 gave the best results in dimethylacetamide (DMA) as solvent and using K C0 as base. The excess of dibromoethane (10 equivalents) required further investigation. Besides being a suspected carcinogen, the large excess of dibromoethane also caused problems during the work-up of the reaction. The reaction mixture, once quenched in water, was extracted with dichloromethane 2


3


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(another solvent to be avoided in production plants). From this extract the solvents and excess dibromoethane were evaporated giving an oily residue, still containing some dibromoethane, from which the product precipitated after addition of water. The residual quantity of dibromoethane in the residue was critical and prevented precipitation of the product when exceeded 30% by weight. When the excess of dibromoethane was reduced to 2 equivalents these problems were solved; the work-up was simplified and made more robust. Furhtermore, instead of precipitating, the product crystallized from the reaction mixture after addition of water. A drawback of working with 2 equivalents of dibromoethane was that the isolated product contained 4 to 8% of compound 19 (Figure 2) whereas with 10 equivalents this amount was only 2 to 3%. This problem was solved by recrystallizing the crude, wet productfromtoluene to give the bomoethyl ether 17 in 62% yield and a purity exceeding 98%.

CI

Figure 2; Structure of double alkylation product

Zinc-Mediated Ring Closure The crucial step in this approach was the ring closure of the dibromo derivative 17 to the dihydrobenzofuran 18. Ring closure of ortho brominated 2haloethylphenylethers using Mg or Li to the corresponding 2,3dihydrobenzofurans is well documented in literature.[i¥-i5] These reagents however are not compatible with the other functional groups in our substrate. Organozinc reagents are known to have a high functional group compatibility. [19] Moreover, cross coupling reactions catalyzed by organozinc reagents are well known.[/9,20] These data prompted us to investigate a zinc mediated ring closure of 17. Direct insertion of zinc into an organic halide is known to be difficult [21, 22] and zinc needs to be activated.[iP, 23, 24] In our case, initial experiments showed that the reaction proceeded even without zinc activation and that addition of transition metals, such as Pd, did not improve the



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conversion. These experiments were run under a nitrogen atmosphere in DMA using 1.1 to 1.3 equivalents of zinc at 40 - 80 °C. Lower conversions were obtained in tetrahydrofuran (THF). A typical conversion is shown in Table 3, the structures of the impurities are outlined in Figure 3. Use of zinc powder (

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