WO1998009988A1

WO1998009988A1 - Process to prepare pharmaceutical compounds

Info

Publication number: WO1998009988A1
Application number: PCT/US1997/015626
Authority: WO
Inventors: Michael J. Martinelli; Eric D. Moher
Original assignee: Eli Lilly And Company; University Of Hawaii; Wayne State University
Priority date: 1996-09-06
Filing date: 1997-09-05
Publication date: 1998-03-12
Also published as: JP2001500496A; AU4182197A; BR9712805A; KR20010029474A; HUP0000291A2; IL128497A0; CA2264245A1; HUP0000291A3; EP0956295A1; EP0956295A4; US6252064B1

Abstract

This invention provides a process for preparing diastereomerically pure cryptophycin compounds.

Description

PROCESS TO PREPARE PHARMACEUTICAL COMPOUNDS

This invention relates to the fields of pharmaceutical and organic chemistry and provides a process for preparing cryptophycin compounds . Cryptophycin compounds are useful anti icrotubule agents. Such compounds can be useful for the treatment of cancer and neoplasms, and are thus useful pharmaceutical agents.

The cryptophycin compounds are known to exist as the epoxide, styrene, and chlorohydrin with reference to the R¹ and R² substituents in Formula I.

(substituents defined as in Formula II infra )

The synthesis of cryptophycin compounds typically results in the compound Formula I compound wherein R^: and R² form a second bond (the styrene form) . The styrene can be converted to the corresponding epoxide (R¹ and R² together form the epoxide) . The epoxide can be stereoselectively opened using a number of nucleophiles, affording an S_N -like inversion at the benzylic position.

However, the corresponding epoxide exists in two diastereomeric forms, as does the corresponding chlorohydrin (R¹⁼C1; R=0H) . Often only one chlorohydrin diastereomer, such as Formula II infra, is desired.

Unfortunately, the separation of epoxide diastereomers required the use of high performance liquid chromatography . Separations requiring the use of high performance liquid chromatography are generally undesirable for large scale or commercial production of products.

The present invention provides a process for preparing the chlorohydrin diastereomer of Formula II directly without having to isolate the corresponding epoxide diastereomers. The process not only eliminates a purification step, but it also provides a process wherein the isolation of the desired chlorohydrin can be completed using normal phase/normal pressure chromatography. Thus, the process of this invention provides an efficient one-pot process for the preparation of a diastereomerically pure compound of Formula II:

II wherein

G is C₁-C₁₂ alkyl, C₂-C_1? alkenyl, C₂-Cι_? alkynyl or Ar; Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group;

R³ is Cι-C₆ alkyl;

R⁴ and R⁵ are H; or

R⁴ and R⁵ taken together form a second bond between C-13 and C-14;

R⁷ is H, Cι-C₆ alkyl NR⁵¹R⁵², - (C]-C₃-alkyl ) NR R⁵², or OR⁵¹; and

R⁸ is H or Cι-C₆ alkyl; or

R⁷ and R⁸ together form a cyclopropyl ring;

R⁵¹ and R⁵² independently are C₁-C3 alkyl; R⁹ is H, Cι-C₆ alkyl, C -C₆ alkenyl, C -C₆-alkynyl or (Cι-C_b alkyl) C₃-C₅ cyeloalkyl;

R¹⁰ is H or Cι-C₆ alkyl;

X is 0, NH or (d-Ca alkyl ) N- ;

Y is C, 0, NH, S, SO, S0₂ or (C1-C3 alkyl) N-; R⁶ is Cι-C₆ alkyl, substituted (C,-C₆) alkyl, (C₃- C₈) cyeloalkyl, substituted C₃-C_H cyeloalkyl, a heteroaromatic or substituted heteroaromatic group, or a group of formula Ilia, III' or III' ' :

R , R , and R^βc independently are H, halo or OR^lb;

R¹⁵, R¹⁶, and R¹⁷ independently are hydrogen, halo, (Cι^~

C₆) alkyl, OR¹⁸, O-aryl, NH₂, NR¹⁸R¹⁹, N0₂, OP0₄H,, (Cι-C₆ alkoxy) phenyl, Sbenzyl, CONH₂, C0₂H, P0₃H,, SO_?R²³, or Z ' ; R¹⁸ and R¹⁹ independently are hydrogen or Cι-C_b alkyl;

R²³ is hydrogen or (Cι-C₃) alkyl;

Z is -(CH₂)„- or (C3-C5) cyeloalkyl; n is 0, 1, or 2; and

Z' is an aromatic or substituted aromatic group; comprising

1) reacting a compound of Formula III

III with ra-chloroperbenzoic acid (m-CPBA) ;

2) reacting the product with trimethylsilyl chloride; and 3) isolating the Formula II compound using flash chromatography .

The term "flash chromatography" is understood in the art. For example, flash chromatography can be completed using Siθ₂ as the medium. The term "alkyl" refers to an alkyl group with the designated number of carbon atoms. It may be saturated or unsaturated, and branched or straight chain. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, propenyl, sec-butyl, n-pentyl, isobutyl, tert-butyl, sec-butyl, methyl-substituted butyl groups, pentyl, tert-pentyl, sec-pentyl, methyl-substituted pentyl groups and the like.

"Substituted alkyl" refers to a Cι-C_D alkyl group that may include up to three (3) substituents containing one or more heteroatoms. Examples of such substituents are OH,

NH₂ , CONH , C0₂H, P0₃H₂ and S 0_?R^{Z 1} wherein R 52^1 i s hydrogen , C C₃ alkyl or aryl.

The term "cyeloalkyl" refers to a saturated C-,-C& cyeloalkyl group. A "substituted cyeloalkyl group" refers to a cyeloalkyl group having up to three

alkyl, halo, or OR²¹ substituents. The substituents may be attached at any available carbon atom. Cyclohexyl is an especially preferred cyeloalkyl group.

"Lower alkoxy" means a Ci-C^ alkyl group bonded to an oxygen atom. The term "halo" refers to Cl, Br, F, or I .

The terms "aromatic group" and "heteroaromatic group" refer to common aromatic rings having 4n + 2 pi electrons in a monocyclic or bicyclic conjugated system. The term "aryl" refers to an aromatic group, and the term "aralkyl" refers to an aryl (Cι-C₆-alkyl ) group. Examples of aromatic groups are phenyl, benzyl and naphthyl . Heteroaromatic groups will contain one or more oxygen, nitrogen and/or sulfur atoms in the ring. Examples of heteroaromatic groups include furyl, pyrrolyl, thienyl, pyridyl and the like. When the aromatic or heteroaromatic groups are substituted, they may have from one to three independently selected C1-C7 alkyl, Cι-C₆-alkoxy or halo substituents. The substituents may be attached at any available carbon atom. Especially preferred heterocyclic groups are

wherein R²⁰ is hydrogen or Cι-C₆ alkyl.

The process of this invention is preferably carried out in the presence of a solvent. The skilled artisan can select appropriate solvents using standard methodologies .

The reaction time is related to the starting materials and operating temperature. The optimum reaction time for a given process is, as always, a compromise which is determined by considering the competing goals of throughput, which is favored by short reaction times, and maximum yield, which is favored by long reaction times.

An especially preferred compound of Formula II is cryptophycin 55 (II) . In this process, it is separated from the less preferred isomer, cryptophycin epi-55. These are prepared from the preferred formula III compound cryptophycin 51. The formula II compounds are prepared via epoxide intermediates, such as cryptophycins 52 and 53. The structures of these compounds are as follows:

CRYPTOPHYCIN 51

CRYPTOPHYCIN 52 CRYPTOPHYCIN 53

CRYPTOPHYCIN 55 CRYPTOPHYCIN epl-55

The following example is to illustrate the method of this invention.

Example 1 Preparation of Cryptophycin 55

A solution of the olefin cryptophycin 51 (2.15 g, 3.29 mmol) in CH₂CI₂ (11 mL) was cooled to 0 °C under nitrogen. m-CPBA (596 mg, 3.45 mmol) was added, and the solution was allowed to stir at 0 °C for 30 min, then at room temperature for 19.5 h. The reaction mixture was then diluted with CHCI₃

(55 mL) and cooled to -60 °C. Chlorotrimethylsilane (TMS- Cl) (1.67 mL, 13.2 mmol) was then added dropwise, and the resulting mixture was stirred at the same temperature for 45 min. Another aliqout of TMS-C1 was added with continued stirring for a further 1.5 h. The reaction mixture was concentrated to dryness in vacuo and flash chromatographed over Siθ₂ with hexane:EtOAc (1:1 to 1:2 to 1:3).

Cryptophycin 55 was isolated as a white foam, 1.18 g, 51?,.

Claims

1. A process for preparing a compound of Formula

II

II wherein

G is C1-C12 alkyl, C₂-C₁₂ alkenyl, C₂-Cι₂ alkynyl or Ar;

Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group;

R³ is Cι-C₆ alkyl;

R* and R⁵ are H; or

R⁴ and R⁵ taken together form a second bond between C-13 and

C-14; R⁷ is H, Cι-C₆ alkyl NR⁵¹R⁵², - (Cι-C₃-al yl) NR⁵¹R⁵², or OR⁵¹; and

R^B is H or Cι-C₆ alkyl; or

R⁷ and R^β together form a cyclopropyl ring;

R⁵¹ and R⁵² independently are C₁-C₃ alkyl;

R⁹ is H, Cι-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆-alkynyl or (Cι-C₆ alkyl) C₃-C₅ cyeloalkyl; R¹⁰ is H or Cι-C₆ alkyl;

X is 0, NH or (Cι-C₃ alkyl)N-;

Y is C, 0, NH, S, SO, S0₂ or (C1-C3 alkyl )N-;

R⁶ is Cι-C₆ alkyl, substituted (Cι-C₆) alkyl, (C₃-

C₈) cyeloalkyl, substituted C₃-C₈ cyeloalkyl, a heteroaromatic or substituted heteroaromatic group, or a group of formula

Ilia, III' or III' ' :

R^6a, R*, and R^6c independently are H, halo or OR¹⁸; R¹⁵, R¹⁶, and R¹⁷ independently are hydrogen, halo, (Cj-

C₆) alkyl, OR¹⁸, O-aryl, NH₂, NR¹⁸R¹⁹, N0₂, OP0₄H₂, (Ci-Cβ alkoxy) phenyl, Sbenzyl, C0NH₂, C0₂H, P0₃H₂, S0₂R²³, or Z';

R¹⁸ and R¹⁹ independently are hydrogen or ) - C alkyl;

R²³ is hydrogen or (Cj-C₃) alkyl; Z is -(CH₂)_n- or (C3-C5) cyeloalkyl; n is 0, 1, or 2; and

Z' is an aromatic or substituted aromatic group; comprising

1) contacting a compound of Formula III

with m-chloroperbenzoic acid;

2) reacting the product with trimethylsilyl chloride; and 3) isolating the Formula II compound using flash chromatography.

2. A process of Claim 1 wherein Ar is an aromatic or substituted aromatic group.

3. A process of Claim 2 wherein Ar is phenyl

4. A process of Claim 1 wherein the flash chromatography process uses Siθ₂.

5. The process of Claim 3 wherein the compound of Formula II is Cryptophycin 55.

CRYPTOPHYCIN 55