WO2010078250A1

WO2010078250A1 - Synthesis of (2-amino)-tetrahydrocarbazole-propanoic acid

Info

Publication number: WO2010078250A1
Application number: PCT/US2009/069586
Authority: WO
Inventors: Yuan WEI; Tianqiao Li; Yongxiang Chi; Jingyang Zhu
Original assignee: Chiral Quest, Inc.
Priority date: 2008-12-30
Filing date: 2009-12-28
Publication date: 2010-07-08
Also published as: JP2012514005A; CN102271505A

Abstract

The present invention provides a new approach to the synthesis of 2-amino-tetrahydrocarbazole-propanoic acid, a key intermediate for the synthesis of Ramatroban. More specifically, a synthesis of 2-amino-tetrahydrocarbazole- propanoic acid which includes oxidizing an aminocyclohexanol to form an aminocyclohexanone, condensing the aminocyclohexanone to form a tetrahydrocarbazole, deprotecting the tetrahydrocarbazole to yield a racemic mixture of a tetrahydrocarbazole, resolving the racemic mixture to obtain a yield mixture with an enantiomeric excess of one enantiomer over another, alkylating the excess enantiomer to yield an alkyl ester, and hydrolyzing the alkyl ester to yield 2-amino-tetrahydrocarbazole-propanoic acid.

Description

SYNTHESIS OF (2-AMINO)-TETRAHYDROCARBAZOLE-PROPANOIC ACID

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of United States Provisional Patent Application Number 61/150,335, filed on February 6, 2009 and United States Provisional Patent Application Number 61/141,527, filed on December 30, 2008, both of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] This invention relates to 2-amino- tetrahydrocarbazole-propanoic acid and a new process for its synthesis .

[0003] 2-Amino-tetrahydrocarbazole-propanoic acid is a key intermediate for the synthesis of Ramatroban, a thromboxaneA2 receptor (TP) antagonist with clinical efficacy in asthma and allergic rhinitis.

Ramatroban l-Amino-tetrahydrocarbazole-proanoic acid

[0004] US Patent 4988820 discloses the synthesis of this compound stating from compound 1, which is condensed with phenylhydrazine and ring-closed to give indole 2. Deprotection of 2 using acid provides ketone 3. Reductive amination of ketone with s-phenylethylamine in the presence of tetrabutylammonium borohydride provides compound 4, which undergoes palladium catalyzed hydrogenation to give key intermediate 5.

Ramatroban

[0005] The process, however, has disadvantages: the starting material 1 is relatively expensive, and the yield of the amination step is only 40% and needs expensive tetrabutylammonium borohydride as the reducing agent. And also the subsequent hydrogenation provides only 70% of the desired compound 5. [0006] US Patent 4988820 also describes an alternative synthesis of compound 5 starting from compound 6, which is oxidized by chromium trioxide to afford ketone 7. Condensation of compound 7 with phenylhydrazine and ring closure give indole 8. The subsequent hydrolysis using HCl provides indole 9. The intermediate 5 is obtained by resolution of racemic 9 using ( + ) -mandelic acid as the resolving agent.

9 5

[0007] However, this process has crucial disadvantages: the first step oxidation reaction needs the heavy metal reagent chromium trioxide, which is toxic and expensive, and the resolution of indole 9 using (+) -mandelic acid affords only -10 % of compound 5.

[0008] US Patent 5684158 discloses the synthesis of 2- amino-tetrahydrocarbazole-propanoic acid ethyl ester 10 by the alkylation of compound 5 in the presence of about 1 mol of alkali metal hydroxides and phase-transfer catalysts such as potassium hydroxide and benzyltriethylammonium chloride.

[0009] The problem with this reaction is that the insoluble material in the reaction mixture becomes very sticky during the reaction. The reaction mixture must be filtered in hot solvent in order to remove insoluble material during work up and the sticky material tents to block the filtration. [0010] Therefore, there is a great need for a new process for the synthesis of 2-amino-tetrahydrocarbazole- propanoic acid.

SUMMARY OF THE INVENTION

[0011] The present invention provides a new approach to the synthesis of 2-amino-tetrahydrocarbazole-propanoic acid, which uses less expensive stating material and regents, avoids heavy metal oxidant reagents for oxidation, employs a more efficient resolving reagent for resolution and provides an alternative alkylation catalyst to make the work-up process more efficient.

[0012] One aspect of the present invention therefore provides a process for synthesizing a tetrahydocarbazole compound having the structure of Formula IV:

Formula IV

wherein the synthesis includes the steps of:

(1) oxidizing an aminocyclohexanol compound having the structure of Formula I :

Formula I wherein Ri and R2 are independently hydrogen, alkyl, aryl, acyl, alkylaryl, alkyloxyacyl, alkylaminoacyl, imide groups, or Ri and R₂ together with the Nitrogen atom to which they are attached form a dicarboxylic acid imide;

to form an aminocyclohexanone compound having the structure of Formula II:

Formula II;

(2) condensing the compound of Formula II with phenylhydrazine to yield a tetrahydrocarbazole compound having the structure of Formula III:

Formula III

and

(3) deprotecting the compound having the structure of

Formula III to yield a racemic mixture of a tetrahydrocarbazole compounds having the structure of Formula IV.

[0013] Methods according to another embodiment of this aspect of the invention further include the step of (4) resolving the racemic mixture to obtain a yield mixture with an enantiomeric excess of one enantiomer over the other. According to one embodiment the (R) -enantiomer is in excess over the (S) -enantio-mer . According to another embodiment, the (S)- enantiomer is in excess over the (R) - enantiomer. [0014] Methods according to another embodiment of this aspect of the invention further include the step of (5) alkylating the product of step (4) to yield an alkyl ester compound having the structure of Formula V:

Formula V wherein R₃ and R₄ are independently selected from lower alkyl groups, and R3 is preferably ethylene so that the Formula V compound is a propionic acid ester.

[0015] Methods according to yet another embodiment of this aspect of the invention further include the step of (6) hydro-lyzing the ester of Formula V to yield the carboxylic acid of Formula VI :

Formula VI [0016] The present invention also provides a more effective reagent for resolving the racemic mixture of tetrahydrocarbazole compounds having the structure of Formula IV. Resolving methods according to this aspect of the present invention include the steps of (4A) dissolving the racemic mixture of tetrahydro-carbazole compounds having the structure of Formula IV in a solvent for the compounds; and (4B) adding to the solution a resolving reagent selected from DBTA, camphorsulfonic acid and 2, 3, 5, 6-di-O- isopropylidene-2-keto-L-gulonic acid to precipitate an enantiomeric excess of the (R) - enantiomer. An excess of the (S) - enantiomer remains in solution and can also be recovered. [0017] According to one embodiment of this aspect of the present invention, steps (4A) and 4 (B) are repeated to further purify the enantiomer product. According to another embodiment of the present invention, steps (5) and (6) are performed on the product of step (4A) to yield a compound having the structure of Formula IV in high enantiomeric purity. Methods according to one embodiment of this aspect of the present invention provide yield mixtures of compounds having the structure of Formula IV with an enantiomeric excess (ee) of one enantiomer over the other of at least 90% and preferably at least 98%. [0018] The present invention also provides a more efficient alkylation catalyst for alkylating the compound of Formula IV to obtain the ketone compound of Formula V. Alkylation methods according to this aspect of the present invention react the compound of Formula IV with an omega- alkenoic acid ester in organic solvent in the presence of sodium hydride, with or without the presence of a phase transfer catalyst such as benzyltriethylammonium chloride. The preferred omega-alkenoic acid ester is ethyl acrylate. According to one embodiment, the ester is subsequently hydrolyzed to yield a free carboxylic acid.

[0019] A more complete appreciation of the invention and many other intended advantages are explained in the following description referencing the drawings and claims, which disclose the principles of the invention and the best modes which are presently contemplated for carrying them out .

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS [0020] As employed above and throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings: [0021] The term "intermediate" refers to a molecular entity that is formed from the reactants (or preceding intermediates) and reacts further to give the directly observed products of a chemical reaction. Most chemical reactions are stepwise, that is they take more than one elementary step to complete. An intermediate is the reaction product of each of these steps, except for the last one, which forms the final product.

[0022] The term "acyl" as used herein refers to a function group that has the formula RC (=0)-, with a double bond between the carbon and oxygen atoms (i.e. a carbonyl group), and a single bond between R and the carbon. [0023] The term "alkyl" as used herein refers to the radical of saturated aliphatic groups, including straight- chain alkyl groups and branched-chain alkyl groups. [0024] The term "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxy groups include methloxy, ethoxy, propoxy, benzyloxyl and the like. [0025] The term "aryl" as used herein refers to any functional group or substituent derived from a simple aromatic ring. Representative aryl groups include phenyl, thiophenyl, indolyl and the like.

[0026] The present invention provides a new approach to the synthesis of 2-amino-tetrahydrocarbazole-propanoic acid via intermediate compounds having the structure of Formula III, in which Ri and R2 independently represent any acyl or its cyclic forms, alkyloxyacyl, alkylaminoacyl groups, or Ri and R₂ together with the Nitrogen atom to which they are attached form a dicarboxylic acid imide:

Formula III

[0027] Intermediates with the structure of Formula III are derived from intermediates of the general Formula II, which are obtained by the bleach oxidation of the starting materials of general Formula I.

Formula I Formula II [0028] The process can be illustrated by way of example by the following reaction scheme, wherein Ri and R₂ define a ring structure wherein -NRiR₂ defines a phthalimido group:

11 12

13

10 [0029] 4- (Phthalimido) -cyclohexanol 11 is oxidized by bleach in water or organic solvents or a mixture of organic solvents to 4- (phthalimido) -cyclohexanone 12 in the presence of TEMPO or its polymer or its other forms, thus avoiding using a heavy metal oxidant for this step. The subsequent condensation with phenyl-hydrazine and ring closure in boiling acetic acid or other high boiling point solvent between about 50 ⁰C to about 250 ⁰C, preferably between about 80 and about 200 ⁰C provides a racemic mixture of indole 13, which undergoes deprotection to 9 in the presence of acids or bases such as hydrazine.

[0030] For the next step, the racemic mixture is resolved using resolving agents such as DBTA, camphorsulfonic acid and 2, 3, 4, 6-di-0-isopropylidene-2-keto-L-gulonic acid, which are all found to be better resolving regents than mandelic acid, when substituted for mandelic acid in conventional recrystallizations . Particularly, when 2, 3 : 4, 6-di-O- isopropylidene-2-keto-L-gulonic acid is used as the resolving reagent, 45% yield (90% yield, based on available enantiomer) of the desired isomer 5 with 90 ee% is obtained for the first resolution and its ee can be further enriched by recrystallization .

[0031] The subsequent alkylation to 10 is conducted using sodium hydride in organic solvent in the presence or without presence of phase transfer catalyst such as benzyltriethyl- ammonium chloride. The amount of sodium hydride can be up to about one mol or a catalytic amount based on stating material, preferably from about 1 to about 10 % mol. The reaction is completed in about 0.5 h, and then is quenched with acid such as acetic acid. The reaction mixture can be filtered at room temperature, or without filtration for further work-up. [0032] The final reaction step is performed using acid or base in a mixture of water and organic solvents such as lithium hydroxide in THF. After the reaction is completed, the organic solvent is removed under reduced pressure and 2- amino-tetrahydro-carbazole-propanoic acid is precipitated from water by adjustment of pH.

[0033] The following non-limiting examples set forth hereinbelow illustrate certain aspects of the invention. All parts and percentages are by mole percent unless otherwise noted and all temperatures are in degrees Celsius. Reactants were of analytical grade and were used as received.

EXAMPLES

EXAMPLE 1: 4- (Phthalimido) -cyclohexanone [0034] 4- (Phthalimido) -cyclohexanol (146 g) was mixed with AcOEt (1000 mL) , after which and NaBr (8 g) and TEMPO

(0.5 g) was added. 1000 mL of NaClO (10 %) was added in portions and the reaction mixture was adjusted using NaHCθ3 to pH 7- 8 to maintain the temperature between 5 and 20 ⁰C. After the reaction was completed, the aqueous layer was separated and the organic layer was washed with brine (400 mL) and dried over Na2SO₄. The solvent was removed under reduced pressure to give the product as white solid (95 % yield) .

EXAMPLE 2: 3- (Phthalimido) -1 , 2 , 3-tetrahydrocarbazole

[0035] 4- (Phthalimido) -cyclohexanone from Example 1 is mixed with 1000 mL AcOH. Phenylhydrazine (46 g) was added and the reaction mixture was heated to reflux. After the reaction was completed, the mixture was cooled down to room temperature and filtered. The cake was washed with AcOH and dried to give the product (102g) as a light yellow solid.

EXAMPLE 3: 3-amino-l , 2 , 3-tetrahydrocarbazole [0036] 3- (Phthalimido) -1,2, 3-tetrahydrocarbazole (70 g) from Example 2 was mixed with 400 mL methanol and 25 mL hydrazine was added. The mixture was stirred overnight and the solid was filtered off. The filtrate was distilled under reduced pressure and the residue was treated with 200 mL of water. 30 mL HCl (20%) was added and stirred for 5 h. The solid was filtered off and the filtrate was adjusted to pH 11 using NaOH (20%) . The solid was filtered and dried to give 33 g of product as a solid.

EXAMPLE 4: (R) -3-amino-l , 2 , 3-tetrahydrocarbazole

[0037] Rac. 3-amino-l, 2, 3-tetrahydrocarbazole from Example 3 was mixed with 150 mL methanol. 2, 3 : 4, 6-Di-O- isopropylidene-2-keto-L-gulonic acid was added. After the resolution was complete, the solid was filtered and the cake was washed with methanol and dried to give 42 g product with 90 ee%, which was recrystallized to give purified material with > 98 ee%

EXAMPLE 5: Ethyl 3- [ (R) -3-amino-l , 2 , 3-tetrahydrocarbazole-9- 91] Propionate (hemisulphate)

[0038] (R) -3-amino-l, 2, 3-tetrahydrocarbazole (0.1 mol) from Example 4 was mixed with 150 mL THF. Benzyltriethylammonium chloride (0.002 mol) and ethyl acrylate (0.25 mol) were added. The mixture was heated to 50 ⁰C and NaH (0.001 mol) was added. After the reaction was completed within 0.5 h, AcOH (0.001 mol) was added and solvent was removed under reduced pressure. The residue was treated with 100 mL of water/ethanol, and adjusted with H₂SO₄ (10 %) to pH 4. The solid was filtered and dried to give the product as a white solid (90 % yield) .

EX. 6: 3- [ (R) -3-Amino-l, 2, 3-tetrahydrocarbazole-9-91] propanoic acid

[0039] Ethyl 3- [ (R) -3-amino-l, 2, 3-tetrahydrocarbazole propio-nate (hemisulphate) (10 g) from Example 5 was mixed with 100 mL THF. 20 mL LiOH (10 %) was added and the mixture as stirred for 3h. The solvent was removed under reduced pressure and the residue was treated with 50 mL of water, then adjusted to pH 5. The product was isolated as a white solid.

[0040] The foregoing description of the preferred embodiments should be taken as illustrating, instead of limiting, the present invention as defined by the claims. As will be readily appreciated, numerous combinations of all features set forth above can be used without departing from the present invention set forth in the claims. Such variations are not regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims .

Claims

What is claimed is:

1. A process for synthesizing a tetrahydrocarbazole compound having the structure of Formula IV:

Formula IV

wherein the synthesis includes the steps of:

(1) oxidizing an aminocyclohexanol compound having the structure of Formula I :

Formula I

wherein Ri and R2 are independently selected from a group consisting of hydrogen, alkyl, aryl, acyl, alkylaryl, alkyloxyacyl, alkylaminoacyl, imide groups, or Ri and R2 together with the Nitrogen atom to which they are attached form a dicarboxylic acid imide;

to form an aminocyclohexanone compound having the structure of Formula II :

Formula I I

Formula III

and; (3) deprotecting the compound having the structure of

2. The process of claim 1, wherein the synthesis further includes the step of: (4) resolving the racemic mixture to obtain a yield mixture with an enantiomeric excess of one enantiomer over the other.

3. The process of claim 2, wherein the yield mixture includes an excess of the (R) -enantiomer over the (S) -enantiomer .

4. The process of claim 2, wherein the yield mixture includes an excess of the (S) -enantiomer over the (R) -enantiomer

5. The process of claim 2, wherein the resolving method includes the steps of: (4A) dissolving the racemic mixture of tetrahydro-carbazole compounds having the structure of Formula IV in a solvent for the compounds; and (4B) adding to the solution a resolving reagent to precipitate an enantiomeric excess of the (R) or (S) - enantiomer.

6. The process of claim 3, wherein the resolving reagent is selected from the group consisting of DBTA, camphorsulfonic acid and 2, 3, 5, 6-di-0-isopropylidene-2-keto-L-gulonic acid.

7. The process of claim 3, wherein the steps (4A) and (4B) are repeated to further purify the enantiomer product.

8. The process of claim 2, wherein the synthesis further includes the step of: (5) alkylating the product of step (4) to yield an alkyl ester compound having the structure of Formula V:

wherein R3 and R4 are independently selected from lower alkyl groups.

9. The process of claim 8, wherein R₃ is ethylene so that the Formula V compound is a propionic acid ester.

10. The process of claim 8, wherein the alkylation is conducted using an alkylation catalyst.

11. The process of claim 10, wherein the alkylation catalyst is an omega-alkenoic acid ester in organic solvent in the presence of sodium hydride, with or without the presence of a phase transfer catalyst such as benzyltriethylammonium chloride.

12. The process of claim 11, wherein the omega-alkenoic acid ester is ethyl acrylate.

13. The process of claim 8, wherein the synthesis further includes the step of: (6) hydrolyzing the ester of Formula V to yield the carboxylic acid of Formula VI:

wherein R₃ is selected from lower alkyl groups.

14. The process of claim 2, wherein the synthesis further includes the steps of: (5A) alkylating the product of step (4A) to yield an alkyl ester compound having the structure of Formula V, and (6A) hydro-lyzing the ester of Formula V to yield the carboxylic acid of Formula VI in high enantiomeric purity, wherein R₃ and R₄ are independently selected from lower alkyl groups.