WO2002042261A2 - Procede de preparation de α-(3-arylthio)-acetophenones - Google Patents

Procede de preparation de α-(3-arylthio)-acetophenones Download PDF

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Publication number
WO2002042261A2
WO2002042261A2 PCT/US2001/042939 US0142939W WO0242261A2 WO 2002042261 A2 WO2002042261 A2 WO 2002042261A2 US 0142939 W US0142939 W US 0142939W WO 0242261 A2 WO0242261 A2 WO 0242261A2
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WO
WIPO (PCT)
Prior art keywords
compound
formula
methyl
aqueous
iii
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Application number
PCT/US2001/042939
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English (en)
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WO2002042261A8 (fr
WO2002042261A3 (fr
Inventor
Wayne Douglas Luke
Heidi Ann Sanderson
Hua Zheng
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Eli Lilly And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to AU2002228593A priority Critical patent/AU2002228593A1/en
Priority to AU2002228593A priority patent/AU2002228593A8/xx
Publication of WO2002042261A2 publication Critical patent/WO2002042261A2/fr
Publication of WO2002042261A3 publication Critical patent/WO2002042261A3/fr
Publication of WO2002042261A8 publication Critical patent/WO2002042261A8/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms

Definitions

  • R and R' are the same or different hydroxy protecting group; are intermediates to pharmaceutically active compounds (see, e . g. , U.S. Patent No.'s 4,075,227, 4,133,814, 4,418,068, 5 , 552 , 401 and 5, 723 , 474) . According to the procedures described in the above mentioned patents, these intermediates are constructed via the following coupling reaction:
  • reaction is performed neat in, e . g. , pyridine or is performed in the presence of aqueous ethanolic potassium hydroxide. In either case, said reactions are performed in a homogenous aqueous miscible environment .
  • purification of the compound of formula I would typically involve the addition of an organic solvent (aqueous immiscible) to facilitate separation of the product (which is soluble in the organic layer) from the inorganic aqueous soluble impurities.
  • the aqueous layer would typically be removed followed by one or more aqueous acidic and basic extractions of the organic layer to remove residual base and inorganic salts.
  • the present invention relates to a process for preparing a compound of formula I :
  • R 1 and R ⁇ are independently selected from the group consisting of hydrogen and a hydroxy protecting group; which includes reacting a compound of formula II:
  • hydroxy protecting groups include, for example, C ⁇ -Cg alkyl and substituted C -Cg alkyl, including methyl, ethyl, isopropyl, cyclopropyl, methoxymethyl , ethylthiomethyl , fcert-buylthiomethyl , (phenyldi ethylsilyl) methoxymethyl, benzyloxymethyl, p- methoxy-benzyloxymethyl , tert-butoxy-methyl; ethoxyethyl, 1- (2-chloroethoxy) ethyl, 2 , 2 , 2-trichloroethoxymethyl, and 2- (trimethylsilyl) ethyl; phenyl and substituted phenyl groups such as p-chlorophenyl, p-methoxyphenyl, and 2,4- dinitrophenyl; benzyl groups; alkylsilyl groups such as trimethyl- triethyl
  • leaving group refers to an atom, or group of atoms that in the aggregate are susceptible to nucleophilic displacement by a thiolate anion, more specifically, to the thiolate shown below:
  • Examples of such leaving groups include halides such as Cl, Br and I; sulfonates (a group of the general formula OSO2 3 where R 3 is optionally substituted C ⁇ -Cg alkyl or optionally substituted phenyl) such as methanesulfonate or toluenesulfonate; and phosphonates (a group of the general formula OPO2 3 ) such as methyl phosphate, ethyl phosphate or phenyl phosphate .
  • suitable alkaline aqueous solvent refers to a suitable base dissolved in water wherein the resulting mixture sufficiently solubilizes the compound of formula II to afford a medium within which to effect the desired deprotonation, i.e., the desired thiolate formation.
  • suitable base refers to a base that is soluble in water and is sufficiently basic to deprotonate the thiol of formula II.
  • bases that can accomplish this deprotonation are carbonates, bicarbonates, phosphates and hydroxides, for example, lithium, cesium, sodium, potassium or magnesium carbonate, bicarbonate, or hydrogen phosphate, phosphate or hydroxide.
  • aqueous immiscible solvent refers to a solvent or mixture of solvents wherein the resulting mixture is substantially immiscible with water and sufficiently solubilizes the compound of formula III to afford a medium that, at the interface of the aqueous and aqueous immiscible phases, is capable of effecting the desired coupling reaction.
  • aqueous immiscible solvents are readily apparent to the skilled artisan and include methylene chloride, chloroform, 1, 2-dichloroethane, ethyl acetate, isopropyl acetate, amyl acetate, toluene, chlorobenzene, methyl t-butyl ether, mixtures thereof, and the like.
  • the biphasic process of the present invention is illustrated in Scheme 1 below.
  • the present process includes deprotonating the thiol of formula II in an aqueous medium to make an aqueous solution of the thiolate. .
  • the deprotonation may be conducted by adding the thiol, to aqueous base or adding base to an aqueous mixture of the thiol.
  • Initial preparation of the aqueous base is preferable to facilitate dissolution of the base and to control the heat of dissolution when bases like sodium or potassium hydroxide are used.
  • Use of hydroxide bases such as sodium or potassium hydroxide are preferable as the formation of the thiolate with these bases do not result in the generation of gas .
  • the deprotonation is readily effected at ambient temperature.
  • the thiols exhibit relatively low water solubility while the thiolate ions exhibit relatively high water solubility.
  • the deprotonation reaction is preferably stirred until the solution is homogeneous.
  • concentration of the aqueous thiolate solution ranges from 0.8 to 1.5 molar.
  • a solution of the acetophenone III may be prepared by dissolving the acetophenone in a water immiscible solvent, preferably ethyl acetate.
  • Preferred leaving groups include chloride and bromide as the corresponding compounds of formula III are readily prepared by ⁇ -chloronation or bromination of the corresponding acetophenone. ⁇ -
  • Chloroacetophenones is most preferred.
  • the solution concentration ranges from 0.5 to 1 molar.
  • the thiolate and organic solution of III are combined and stirred between 15 and 50°C. While complete reaction is typically achieved in 1 to 3 hours at ambient temperature elevated temperatures may be used to increase solubility of the acetophenone derivative and the reaction product .
  • the phases are separated and the desired product can be crystallized from the organic phase by either concentration or addition of an anti-solvent or a combination of both.
  • the most preferable anti-solvents are heptanes or hexanes .
  • Preferred compounds of formula II for use in the present process are those where R 1 is hydrogen, methyl, isopropyl or benzyl, particularly hydrogen, methyl or benzyl .
  • Preferred compounds of formula III for use in the present process are those where R ⁇ is hydrogen, methyl, isopropyl or benzyl, particularly methyl.
  • preferred products of the above reaction include, but are not limited to, - (3-hydroxyphenylthio) -4-methoxyacetophenone, ⁇ - (3- methoxyphenylthio) -4-methoxyacetophenone, ⁇ - (3- isopropoxyphenylthio) -4-methoxyacetophenone, and ⁇ -(3- benzyloxyphenylthio) -4-methoxyacetophenone .
  • the process of the present invention is performed in a biphasic reaction medium.
  • biphasic reactions are expected to proceed at a diminished rate, relative to the corresponding mono-phasic reaction.
  • biphasic reactions can offer an advantage with product purification. That is, purification is sometimes much simpler and efficient with a biphasic reaction when the product is mostly soluble in one phase and the impurities are mostly soluble in the other.
  • phase transfer catalysts are typically employed in biphasic systems. Surprisingly, the present process proceeds at rates and in yields comparable to the prior art mono-phasic rates even in the absence of a phase transfer catalyst.
  • a compound of formula I is cyclized, acylated, optionally deprotected and optionally salified to form a compound of formula IV:
  • R 3 and R 4 are independently C1-C4 alkyl, or combine together with the nitrogen to which they are attached to form a piperidinyl, pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, morpholino, dimethylamino, diethylamino, or 1-hexamethyleneimino ring.
  • the cyclization, acylation and optional deprotection and salification reactions may be performed essentially as described in U.S. Patent No .
  • a compound of formula I may be cyclized, 3-halogenated, S-oxidized, have the 3- halo group displaced, reduced, optionally deprotected, and optionally salified to prepare a compound of formula V:
  • a compound of formula I may be used to prepare a compound of formula VII and VIII: .
  • hydrochloride salt of compound of formula V where 1 is hydrogen, R 2 is methyl, and R 3 and R 4 combine to form piperidinyl is preferred.
  • Compounds of formula II and III are known in the art and are generally commercially available or can be prepared by methods well known in the art from readily available starting materials.
  • An aqueous solution of potassium hydroxide is prepared by dissolving 4.46 gm of potassium hydroxide flakes in 36.8 ml of water.
  • 8.59 gm of ⁇ -chloro-4- methoxyacetophenone and 50 ml of ethyl acetate are combined and warmed to 35°C to effect dissolution.
  • 7.01 gm of 3-methoxybenzenethiol are added to the aqueous solution of base.
  • the warm ethyl acetate solution of the ⁇ -chloride is added.
  • the resulting bi-phasic reaction mixture is stirred at 30°C for 3 hours. The phases are separated.
  • the desired product is crystallized by dropwise addition of 200 mis of hexane at 20-25°C.
  • the resulting crystalline slurry is cooled to -10°C and stirred for 2 hours.
  • the solids are isolated by filtration, washed with hexane, and dried at 30°C under vacuum overnight to afford 12.44 gm of product. ⁇ ""H and 13 C NMR spectra were consistent with that of the desired product.
  • An aqueous solution of potassium hydroxide is prepared by dissolving 6.28 gm of potassium hydroxide pellets in 50 ml of water. The solution was adjusted to ambient temperature and 10.0 gm of 3-hydroxybenzenethiol was added with a 16.5 ml water rinse. The reaction mixture was stirred for approximately 10 minutes until homogeneous and a solution of 14.64 gm of ⁇ -chloro-4-methoxyacetophenone dissolved in 120 ml of ethyl acetate was added with a 14 ml ethyl acetate rinse.
  • the resulting yellow solution was cooled to 60°C and 400 ml of heptanes were slowly added in a dropwise manner during which time the reaction temperature was allowed to cool to 50°C. This resulted in crystallization of the desired product.
  • the crystalline slurry was allowed to cool to ambient temperature and an additional 400 ml of heptanes was added dropwise over a 1 hour period. The crystalline slurry was stirred for 1 hour.
  • the solids were isolated by filtration, washed with 100 ml of heptanes and dried overnight at ambient temperature with a light nitrogen purge to afford 96.21 gm of product. 1 H and 13 C NMR spectra were consistent with that of the desired product.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation biphasique d'un composé représenté par la formule générale (I) à partir des composés représentés par les formules générales (II) et (III).
PCT/US2001/042939 2000-11-27 2001-11-14 Procede de preparation de α-(3-arylthio)-acetophenones WO2002042261A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2002228593A AU2002228593A1 (en) 2000-11-27 2001-11-14 Process for preparing alpha-(3-arylthio)-acetophenones
AU2002228593A AU2002228593A8 (en) 2000-11-27 2001-11-14 Process for preparing alpha-(3-arylthio)-acetophenones

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US25307300P 2000-11-27 2000-11-27
US60/253,073 2000-11-27

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WO2002042261A2 true WO2002042261A2 (fr) 2002-05-30
WO2002042261A3 WO2002042261A3 (fr) 2003-03-06
WO2002042261A8 WO2002042261A8 (fr) 2008-04-24

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078705A1 (fr) * 2003-03-06 2004-09-16 Basf Aktiengesellschaft Procede de production d'$g(a)-(3-arylthio)-acetophenones
US6921827B2 (en) 2000-11-27 2005-07-26 Eli Lilly And Company Process for preparing 3-aryl-benzo{b} thiophenes
US7964734B2 (en) 2002-09-30 2011-06-21 A/S Gea Farmaceutisk Fabrik Raloxifene acid addition salts and/or solvates thereof, improved method for purification of said raloxifene acid addition salts and/or solvates thereof and pharmaceutical compositions comprising these

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4418068A (en) * 1981-04-03 1983-11-29 Eli Lilly And Company Antiestrogenic and antiandrugenic benzothiophenes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4418068A (en) * 1981-04-03 1983-11-29 Eli Lilly And Company Antiestrogenic and antiandrugenic benzothiophenes

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A.D. PALKOWITZ, ET AL.: "Discovery and synthesis of [6-hydroxy-3-[4-[2-(1- piperdinyl)-ethoxyÜphenoxyÜ-2-(4- hydroxyphenyl)ÜbenzoÄbÜthiophene: a novel, highly potent, selective oestrogen receptor modulator" JOURNAL OF MEDICINAL CHEMISTRY, vol. 40, no. 10, 9 May 1997 (1997-05-09), pages 1407-1416, XP002217620 American Chemical Society, Washington, DC, US ISSN: 0022-2623 *
C.D. JONES, ET AL.: "Antioestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzoÄbÜthiophene derivatives leading to [6-hydroxy-2-(4- hydroxyphenyl)benzoÄbÜthien-3-ylÜ[4-[2-(1- piperidinyl)ethoxyÜphenylÜmethanone hydrochloride (LY156758), a remarkably effective oestrogen anganonist" JOURNAL OF MEDICINAL CHEMISTRY, vol. 27, no. 8, August 1984 (1984-08), pages 1057-1066, XP000560343 American Chemical Society, Washington, DC, US ISSN: 0022-2623 *
S. KIM, ET AL.: "A facile synthesis of 3-aryl-substituted-benzothiophenes via a Lewis acid mediated cyclisation of 2-arylthio-acetophenones" TETRAHEDRON LETTERS, vol. 40, no. 15, 1999, pages 2909-2912, XP001068955 Elsevier Science Publishers, Amsterdam, NL ISSN: 0040-4039 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6921827B2 (en) 2000-11-27 2005-07-26 Eli Lilly And Company Process for preparing 3-aryl-benzo{b} thiophenes
US7964734B2 (en) 2002-09-30 2011-06-21 A/S Gea Farmaceutisk Fabrik Raloxifene acid addition salts and/or solvates thereof, improved method for purification of said raloxifene acid addition salts and/or solvates thereof and pharmaceutical compositions comprising these
WO2004078705A1 (fr) * 2003-03-06 2004-09-16 Basf Aktiengesellschaft Procede de production d'$g(a)-(3-arylthio)-acetophenones
CN100345824C (zh) * 2003-03-06 2007-10-31 巴斯福股份公司 α－(3－芳硫基)苯乙酮的制备方法
US7385087B2 (en) 2003-03-06 2008-06-10 Basf Aktiengesellschaft Method for producing a-(3-arylthio)-acetophenones

Also Published As

Publication number Publication date
AU2002228593A1 (en) 2002-06-03
WO2002042261A8 (fr) 2008-04-24
WO2002042261A3 (fr) 2003-03-06
AU2002228593A8 (en) 2008-06-12

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