(S)-Bicalutamide-d4

Cat. No.: B1140949

CAS No.: 1217769-79-3

M. Wt: 434.4

InChI Key:

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Overview

1. Description

8. Synthesis routes and methods I

2. Scientific research applications

9. Synthesis routes and methods II

3. Preparation methods

10. Synthesis routes and methods III

4. Chemical reactions analysis

11. Synthesis routes and methods IV

5. Mechanism of action

12. Synthesis routes and methods V

6. Comparison with similar compounds

13. Disclaimer

7. Properties

Description

(S)-Bicalutamide-d4 is a deuterated form of (S)-Bicalutamide, a non-steroidal anti-androgen medication primarily used in the treatment of prostate cancer. The deuterium atoms in this compound replace the hydrogen atoms, which can enhance the compound’s metabolic stability and potentially improve its pharmacokinetic properties.

Scientific Research Applications

(S)-Bicalutamide-d4 has several scientific research applications, including:

Chemistry: Used as a reference standard in mass spectrometry due to its deuterium labeling.

Biology: Studied for its effects on androgen receptors and its potential to inhibit androgen-dependent cellular processes.

Medicine: Investigated for its improved pharmacokinetic properties compared to non-deuterated (S)-Bicalutamide, potentially leading to better therapeutic outcomes.

Industry: Utilized in the development of new anti-androgen therapies and as a tool in drug metabolism studies.

Preparation Methods

Synthetic Routes and Reaction Conditions

The synthesis of (S)-Bicalutamide-d4 involves several steps, starting from commercially available starting materials. The key steps include:

Deuterium Exchange Reaction: This involves the replacement of hydrogen atoms with deuterium atoms using deuterated reagents.

Coupling Reactions: These reactions form the core structure of this compound, typically involving palladium-catalyzed cross-coupling reactions.

Purification: The final product is purified using techniques such as recrystallization or chromatography to ensure high purity.

Industrial Production Methods

Industrial production of this compound follows similar synthetic routes but on a larger scale. The process is optimized for efficiency and cost-effectiveness, often involving continuous flow reactors and automated systems to ensure consistent quality and yield.

Chemical Reactions Analysis

Types of Reactions

(S)-Bicalutamide-d4 undergoes various chemical reactions, including:

Oxidation: This reaction involves the addition of oxygen or the removal of hydrogen, often using oxidizing agents like potassium permanganate.

Reduction: This involves the addition of hydrogen or the removal of oxygen, typically using reducing agents such as lithium aluminum hydride.

Substitution: This reaction involves the replacement of one functional group with another, often using nucleophilic or electrophilic reagents.

Common Reagents and Conditions

Oxidation: Potassium permanganate, hydrogen peroxide.

Reduction: Lithium aluminum hydride, sodium borohydride.

Substitution: Halogenating agents, nucleophiles like amines or thiols.

Major Products

The major products formed from these reactions depend on the specific conditions and reagents used. For example, oxidation may yield hydroxylated derivatives, while reduction could produce deuterated alcohols.

Mechanism of Action

(S)-Bicalutamide-d4 exerts its effects by binding to androgen receptors, thereby inhibiting the action of androgens like testosterone. This inhibition prevents the growth and proliferation of androgen-dependent prostate cancer cells. The deuterium atoms in this compound may enhance its binding affinity and metabolic stability, leading to prolonged action.

Comparison with Similar Compounds

Similar Compounds

(S)-Bicalutamide: The non-deuterated form, widely used in clinical settings.

Enzalutamide: Another non-steroidal anti-androgen with a different chemical structure but similar therapeutic use.

Apalutamide: Similar to enzalutamide, used in the treatment of prostate cancer.

Uniqueness

(S)-Bicalutamide-d4 is unique due to its deuterium labeling, which can enhance its metabolic stability and pharmacokinetic properties compared to its non-deuterated counterpart. This can potentially lead to improved therapeutic outcomes and reduced side effects.

Properties

IUPAC Name	(2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-3-(2,3,5,6-tetradeuterio-4-fluorophenyl)sulfonylpropanamide	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

InChI	InChI=1S/C18H14F4N2O4S/c1-17(26,10-29(27,28)14-6-3-12(19)4-7-14)16(25)24-13-5-2-11(9-23)15(8-13)18(20,21)22/h2-8,26H,10H2,1H3,(H,24,25)/t17-/m1/s1/i3D,4D,6D,7D	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

InChI Key	LKJPYSCBVHEWIU-YNWMVSOESA-N	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Canonical SMILES	CC(CS(=O)(=O)C1=CC=C(C=C1)F)(C(=O)NC2=CC(=C(C=C2)C#N)C(F)(F)F)O	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Isomeric SMILES	[2H]C1=C(C(=C(C(=C1F)[2H])[2H])S(=O)(=O)C[C@](C)(C(=O)NC2=CC(=C(C=C2)C#N)C(F)(F)F)O)[2H]	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Molecular Formula	C18H14F4N2O4S	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Molecular Weight	434.4 g/mol	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Synthesis routes and methods I

Procedure details

180 mg of the chiral epoxide of example 17 was dissolved in a mixture of 12 ml chloroform and 12 ml of water. 133 mg of sodium-p-fluorobenzenesulfinate and 107 mg of tetrabutylammonium bromide were added. The reaction mixture was heated till reflux and kept at reflux, while stirring vigorously. The reaction was monitored with HPLC. After 4 days at reflux, the starting epoxide was completely converted. The mixture was cooled to room temperature. 10 ml of chloroform was added. The organic layer was washed with 3×20 ml of water, dried (Na2SO4), filtrated and evaporated to dryness. Residue: 226 mg (brown oil). Purification of the residue by column chromatography (Merck silica gel 60; eluens: heptane/ethyl acetate=1/1) afforded R-enantiomer of bicalutamide as a white/yellow solid material. Purified yield: 122 mg (43%). HPLC: 96.3% purity. HPLC (chiral column): 94.7% e.e. 1H and 13C NMR in agreement with R-bicalutamide

Name

epoxide

Quantity

180 mg

Type

reactant

Reaction Step One

Name

chloroform

Quantity

12 mL

Type

solvent

Reaction Step One

Name

water

Quantity

12 mL

Type

solvent

Reaction Step One

Name

sodium p-fluorobenzenesulfinate

Quantity

133 mg

Type

reactant

Reaction Step Two

Name

tetrabutylammonium bromide

Quantity

107 mg

Type

catalyst

Reaction Step Two

[Compound]

Name

epoxide

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Three

Name

chloroform

Quantity

10 mL

Type

solvent

Reaction Step Four

Name

bicalutamide

Details

Synthesis routes and methods II

Procedure details

0.500 g of the epoxyamide (5A) was dissolved in a mixture of 40 ml of chloroform and 40 ml of water and 371 mg of sodium p-fluorobenzenesulfinate was added. Subsequently, 298 mg of tetrabutylammonium bromide was added. The reaction mixture was heated till reflux, while stirring vigorously. The reaction was monitored with HPLC. After 96 hours of reflux, the reaction mixture was cooled to room temperature. 20 ml of chloroform was added and the organic layer was washed with 3×50 ml of water, dried (Na2SO4) and evaporated to dryness. Yield: 860 mg. Purification of the crude product by column chromatography (Merck silica gel 60; eluent: heptane/ethyl acetate=1/1) afforded bicalutamide as white solid. Isolated yield: 380 mg (48%). 1H-NMR: confirmed the structure.

Name

epoxyamide

Quantity

0.5 g

Type

reactant

Reaction Step One

Name

sodium p-fluorobenzenesulfinate

Quantity

371 mg

Type

reactant

Reaction Step One

Name

chloroform

Quantity

40 mL

Type

solvent

Reaction Step One

Name

water

Quantity

40 mL

Type

solvent

Reaction Step One

Name

tetrabutylammonium bromide

Quantity

298 mg

Type

catalyst

Reaction Step Two

Name

chloroform

Quantity

20 mL

Type

solvent

Reaction Step Three

Name

bicalutamide

Details

Synthesis routes and methods III

Procedure details

4′-Cyano-3-(4-fluorophenylthio)-2-hydroxy-2-methyl-3′-trifluoromethylpropionanilide (12.20 g, 30.6 mmol) and ethyl acetate (20 ml) were successively charged in a 200 ml four-neck flask, and the mixture was stirred under ice-cooling (2° C.–7° C.). A solution of mono-perphthalic acid in ethyl acetate (166.58 g, net 22.31 g, 122.5 mmol) was dropwise added at not higher than 10° C., and the mixture was stirred for 1 hr. A 20% KOH solution (117.5 g) was dropwise added thereto and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate (30 ml). The combined organic layer was washed with a solution of sodium pyrosulfite (3.0 g) dissolved in deionized water (30 ml), dried over magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (66 ml) was added to the residue and the mixture was heated to 60° C. n-Heptane (40 ml) was added dropwise at a temperature of 60° C.–65° C. over 40 min. After the completion of the dropwise addition, the mixture was allowed to cool to room temperature (about 20° C.–25° C.) and filtrated to give 4′-cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3′-trifluoromethylpropionanilide (12.24 g, yield 91.2%). Purity 99.97%.

Name

4′-Cyano-3-(4-fluorophenylthio)-2-hydroxy-2-methyl-3′-trifluoromethylpropionanilide

Quantity

12.2 g

Type

reactant

Reaction Step One

Name

ethyl acetate

Quantity

20 mL

Type

solvent

Reaction Step One

Name

mono-perphthalic acid

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Two

Name

ethyl acetate

Quantity

166.58 g

Type

solvent

Reaction Step Two

Name

KOH

Quantity

117.5 g

Type

reactant

Reaction Step Three

Name

4′-cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3′-trifluoromethylpropionanilide

Yield

91.2%

Details

Synthesis routes and methods IV

Procedure details

Name

[Br-]

Quantity

Extracted from reaction SMILES

Type

reactant

Reaction Step One

Name

CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1

Quantity

Extracted from reaction SMILES

Type

reactant

Reaction Step One

Name

CCCC[N+](CCCC)(CCCC)CCCC

Quantity

Extracted from reaction SMILES

Type

reactant

Reaction Step One

Name

ClC(Cl)Cl

Quantity

Extracted from reaction SMILES

Type

reactant

Reaction Step One

Name

O=S([O-])c1ccc(F)cc1

Quantity

Extracted from reaction SMILES

Type

reactant

Reaction Step One

Name

[Na+]

Quantity

Extracted from reaction SMILES

Type

reactant

Reaction Step One

Name

Quantity

Extracted from reaction SMILES

Type

reactant

Reaction Step One

Name

CC(O)(CS(=O)(=O)c1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Details

Synthesis routes and methods V

Procedure details

To a solution of 2 g (2.51 mmol) of N-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenyl-thio]-2-hydroxy-2-methyl-propionamide in 10 ml of acetonitrile, 20 ml of methanol and 0.6 ml of water 0.38 g (2.75 mmol) of potassium carbonate was added. The mixture was cooled to 5° C. and 10 ml of 30% aqueous hydrogen peroxide solution was added dropwise. The mixture was stirred at 25° C. overnight, then diluted with 100 ml of water and extracted twice with 100 ml of dichloromethane. The organic layer was washed with 50 ml of brine, dried over sodium sulfate and concentrated under diminished pressure. The residue was recrystallized from a 1:4 mixture of ethyl acetate/petroleum ether, which has a boiling range of 40–70° C. The yield was 1.53 g (70.83%).

Name

N-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenyl-thio]-2-hydroxy-2-methyl-propionamide

Quantity

2 g

Type

reactant

Reaction Step One

Name

potassium carbonate

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

water

Quantity

0.6 mL

Type

reactant

Reaction Step One

Name

acetonitrile

Quantity

10 mL

Type

solvent

Reaction Step One

Name

methanol

Quantity

20 mL

Type

solvent

Reaction Step One

Name

hydrogen peroxide

Quantity

10 mL

Type

reactant

Reaction Step Two

Name

water

Quantity

100 mL

Type

reactant

Reaction Step Three

Name

N-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenyl-sulfonyl]-2-hydroxy-2-methyl-propionamide

Details

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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.

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