SYNTHETIC ROUTE TO SCOPOLAMINE AND/OR ATROPINE

Abstract

A synthetic route to scopolamine and/or atropine. In such context, the present invention identifies a method for preparing 6,7-dehydro atropine, which can be converted into either scopolamine and/or atropine, along with a method for converting a protected pyrrole into a tetrachlorobicylic compound, such as benzyl 3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate.

Claims

1. A method for preparing 6,7-dehydro atropine comprising: (a) providing a protected pyrrole having the following formula: ##STR00021## wherein R may be an alkyl group, phenyl group, or benzyl group; (b) reacting the protected pyrrole with pentachloroacetone and forming a first tetrachloro-bicyclic compound having the following formula: ##STR00022## wherein R may be an alkyl group, phenyl group, or benzyl group; (c) carrying out a reductive dechlorination of said first tetrachloro-bicyclic compound and forming a second bicyclic compound having the following formula: ##STR00023## wherein R may be an alkyl group, phenyl group, or benzyl group; (d) carrying out a reductive methylation of the second bicyclic compound formed in step (c) and forming or 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol having the following formula: ##STR00024## (e) converting 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol into 6,7-dehydro tropine tosylate having the following formula: ##STR00025## wherein —OTs is reference to —OSO.sub.2—Ar—CH.sub.3; and (f) converting 6,7-dehydro tropine tosylate into 6,7-dehydro atropine having the following formula: ##STR00026##

2. The method of claim 1 wherein 6,7-dehydro atropine is converted by oxidation into scopolamine having the following formula: ##STR00027##

3. The method of claim 2 wherein said oxidation of 6,7-dehydro atropine occurs in the presence of manganese sulfate, hydrogen peroxide and sodium bicarbonate.

4. The method of claim 1 wherein 6,7-dehydro atropine is converted by reduction into atropine having the following formula: ##STR00028##

5. The method of claim 4 wherein said reduction of 6,7-dehydroatropine occurs by diimide reduction wherein hydrazine is oxidized to a diimide in situ.

6. The method of claim 1 wherein R is a benzyl group, said first tetrachloro-bicyclic compound comprises benzyl 2,2,4,4-tetrachloro-3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate and said second bicyclic compound comprises benzyl 3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate.

7. The method of claim 1 wherein in step (b), said reaction of said pyrrole with pentachloroacetone takes place in the presence of N-methylmorpholine.

8. The method of claim 1 wherein in step (b), pentachloroacetone is provided in situ from hexachloroacetone.

9. A method of converting a converting a protected pyrrole into a tetrachlorobicylic compound comprising: a. providing a protected pyrrole having the following formula: ##STR00029## wherein R may be an alkyl group, phenyl group, or benzyl group; b. reacting the protected pyrrole with pentachloroacetone and forming a tetrachloro-bicyclic compound having the following formula: ##STR00030## wherein R may be an alkyl group, phenyl group, or benzyl group.

10. The method of claim 9 wherein pentachloroacetone is provided in situ from hexachloroacetone.

11. The method of claim 9, wherein R is a benzyl group and said tetrachlorobicyclic compound comprises benzyl 3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate.

12. A method for preparing scopolamine comprising: (a) providing a protected pyrrole having the following formula: ##STR00031## wherein R may be an alkyl group, phenyl group, or benzyl group; (b) reacting the protected pyrrole with pentachloroacetone, wherein said pentachloroacetone is provided in situ from hexachloroacetone and forming a first tetrachloro-bicyclic compound having the following formula: ##STR00032## wherein R may be an alkyl group, phenyl group, or benzyl group; (c) carrying out a reductive dechlorination of said first tetrachloro-bicyclic compound and forming a second bicyclic compound having the following formula: ##STR00033## wherein R may be an alkyl group, phenyl group, or benzyl group; (d) carrying out a reductive methylation of the second bicyclic compound formed in step (c) and forming or 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol having the following formula: ##STR00034## (e) converting 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol into 6,7-dehydro tropine tosylate having the following formula: ##STR00035## wherein —OTs is reference to —OSO.sub.2—Ar—CH.sub.3; and (f) converting 6,7-dehydro tropine tosylate into 6,7-dehydro atropine having the following formula: ##STR00036## and (g) converting 6,7-dehydro atropine by oxidation into scopolamine having the following formula: ##STR00037##

13. The method of claim 12 wherein said oxidation of 6,7-dehydro atropine occurs in the presence of manganese sulfate, hydrogen peroxide and sodium bicarbonate.

14. A method for preparing atropine comprising: (a) providing a protected pyrrole having the following formula: ##STR00038## wherein R may be an alkyl group, phenyl group, or benzyl group; (b) reacting the protected pyrrole with pentachloroacetone, wherein said pentachloroacetone is provided in situ from hexachloroacetone and forming a first tetrachloro-bicyclic compound having the following formula: ##STR00039## wherein R may be an alkyl group, phenyl group, or benzyl group; (c) carrying out a reductive dechlorination of said first tetrachloro-bicyclic compound and forming a second bicyclic compound having the following formula: ##STR00040## wherein R may be an alkyl group, phenyl group, or benzyl group; (d) carrying out a reductive methylation of the second bicyclic compound formed in step (c) and forming or 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol having the following formula: ##STR00041## (e) converting 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol into 6,7-dehydro tropine tosylate having the following formula: ##STR00042## wherein —OTs is reference to —OSO.sub.2—Ar—CH.sub.3; and (f) converting 6,7-dehydro tropine tosylate into 6,7-dehydro atropine having the following formula: ##STR00043## and converting 6,7-dehydro atropine by reduction into atropine having the following formula: ##STR00044##

15. The method of claim 14 wherein said reduction of 6,7-dehydro atropine occurs by diimide reduction wherein hydrazine is oxidized to diimide in situ.

Description

BRIEF DESCRIPTION OF THE DRAWING

[0019] FIG. 1. illustrates the oxidation of compound 7, 6,7-dehydro atropine, followed by a reductive work-up.

DETAILED DESCRIPTION

[0020] The present invention is directed to a synthetic route to scopolamine and/or atropine. In the initial step, a protected pyrrole is provided. One can therefore utilize an alkyl, phenyl or benzyl carbamate protected pyrrole which can be achieved by treatment of pyrrole with a substituted chloroformate Cl—CO—OR, where R can be an alkyl group (e.g. methyl, ethyl propyl), a phenyl group, a substituted phenyl group, or a benzyl group:

##STR00011##

[0021] Preferably, the pyrrole herein is protected by treatment with sodium hydride followed by quenching upon addition of benzyl chloroformate (ClCOOBn) at −78° C., in a preferred tertiary butanol (tBuOH) and tetrahydrofuran (THF) solvent media, to yield a benzyl carbamate protected pyrrole at yields of around 95%:

##STR00012##

[0022] In the next step shown below, the preferred benzyl carbamate protected pyrrole 2 is reacted with pentachloroacetone (PCA or Cl.sub.3COC(Cl).sub.2H) in the preferred solvent hexfluroisopropanol (HFIPA) in the presence of the preferred organic base N-methylmorpholine (NMM), which organic base is preferably at a concentration of 0.5 M, providing the compound 3, benzyl 2,2,4,4-tetrachloro-3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate, in 86% yield:

##STR00013##

[0023] With regards to the use of pentachloracetone (PCA) for the conversion of compound 2 to compound 3, it was recognized herein that the PCA can be preferably prepared from hexachloroacetone (HCA), in situ, in the presence of a trialkyl- or triaryl- phosphite having the formula POR.sub.3 where R can be an alkyl group (e.g., methyl, ethyl, propyl) or a phenyl moiety. A particularly preferred phosphite is triphenyphosphite (P(OPh).sub.3). In addition, one may utilize a trialkyl- or triaryl phosphine having the formula PR.sub.3 where R can again be alkyl groups (e.g., methyl, ethyl propyl) or a phenyl moiety.

[0024] Reductive dechlorination of benzyl 2,2,4,4-tetrachloro-3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate provides compound 4, benzyl 3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate, in greater than 90% yield. More specifically, compound 3 is exposed to a reducing agent, preferably Zn, a tertiary amine (NR.sub.3 wherein R is an alkyl group such as a methyl, ethyl and/or propyl group), more preferably tetramethylene diamine (TMEDA), an organic acid such as acetic acid (AcOH), in an organic alcohol such as methanol (MeOH) according to the following reaction scheme:

##STR00014##

[0025] Reductive methylation of compound 4 and formation of a tosylate salt follows. Preferably, compound 4 is reacted in tetrahydrofuran solvent (THF) in the presence of dibutyl aluminum hydroxide (DIBAL-H) to reduce the ketone moiety followed by addition of lithium aluminum hydride (LiALH.sub.4) to reduce the carbamate, at preferred reaction temperatures of −78° C. to room temperature (r.t.), resulting in compound 5 (6-tropen-3α-ol or 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol), at yields of at or over 80%:

##STR00015##

[0026] Compound 5 is then treated with p-toluene sulfonic acid (pTSA) in a preferred acetone solvent which provides compound 6, 6,7-dehydro tropine tosylate, at yields of at or over 65%. In the formula below, —OTs is reference to —OSO.sub.2—Ar—CH.sub.3:

##STR00016##

[0027] Compound 6 is then converted to compound 7, 6,7-dehydro atropine, at yields of at or above 80.0%. Specifically, coupling of tropic acid to compound 6 was preferably achieved by use of tropic acid having an organo-silicon protective group. One therefore preferably employs a tertbutyldimethylsilyl (TBS) protected tropic acid which then can reduce the risk of side reactions that may occur during its removal. This coupling reaction preferably proceeds in the presence of methylnitrobenzoic acid anhydride (MNBA), triethyl amine (TEA), in an organic solvent, such as methylene chloride. Then, deprotection of the organo-silicon protective group proceeds via the use of methanol (MeOH) buffered with acetic acid (AcOH) in the presence of ammonium fluoride (NH.sub.4F).

##STR00017##

[0028] Compound 7, 6,7-dehydro atropine, can then be converted into compound 8, scopolamine and/or compound 9, atropine. The conversion to scopolamine preferably proceeds via oxidation of compound 7 in an organic solvent. Preferably, oxidation in the presence of manganese sulfate (MnSO.sub.4) and hydrogen peroxide (H.sub.2O.sub.2) in an organic solvent (DMF) in the presence of sodium bicarbonate followed by a reductive work-up with sodium hydrogen sulfite (NaHSO.sub.3) in methanol (MeOH), which provides a 25% yield of scopolamine (46% based on recovered starting material). The reductive work-up with NaHSO.sub.3 reduced the amine oxides of compound 7, 8, 9 back to the corresponding amines. The general scheme is set out below. The more specific scheme is illustrated in FIG. 1.

##STR00018##

[0029] In addition, it is contemplated that the MnSO.sub.4 in the above reaction scheme may be utilized, preferably at a 1:1 molar ratio, with a ligand, from the family of porphyrin, diamine and picolinic acid compounds illustrated below, where R may be an alkyl group (e.g., methyl, ethyl, propyl) or an aryl group:

##STR00019##

[0030] As alluded to above, compound 7, 6,7-dehydro atropine may also undergo reduction into compound 9, atropine. Preferably, one can employs a diimide reduction, where the diimide is provide from hydrazine (H2N2), in the presence of copper sulfate (CuSO.sub.4) in ethanol (EtOH) media, which provides atropine at yields of 50%. The role of the CuSO.sub.4 catalyst is to oxidize hydrazine to diimide in situ:

##STR00020##

[0031] As may now be appreciated, the present invention identifies a new synthetic pathway, that allows for the ability to isolate scopolamine and/or atropine (OPNA antidotes) at the indicated yields, and in a limited number of steps, from pyrrole. Such synthetic pathway offers what is contemplated to be a significant improvement over current procedures for isolating such antidotes, an example of which is now circumventing the reliance on Duboisia leichhardtii as the source of scopolamine, while more efficiently meeting expanding global demands of nerve agent remedies.