CN102584744B - Synthesis method of 4-(4-((2-(4-chlorophenyl)-5,5-dimethyl cyclohexyl-1-polyprolene) methyl) diethylenediamine-1-radical) benzoic acid - Google Patents
Synthesis method of 4-(4-((2-(4-chlorophenyl)-5,5-dimethyl cyclohexyl-1-polyprolene) methyl) diethylenediamine-1-radical) benzoic acid Download PDFInfo
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Abstract
The invention relates to an improved synthesis method of the intermediate carboxylic acid segment [4-(4-((2-(4-chlorophenyl)-5,5-dimethyl cyclohexyl-1-polyprolene) methyl) diethylenediamine-1-radical) benzoic acid] of an anticancer compound molecule ABT-263. The synthesis method mainly solves the problems of complicated operation, low yield and high synthesis cost of the existing synthesis method. The synthesis of the intermediate carboxylic acid segment of ABT-263 comprises the following steps: step 1, the reaction takes 4,4-dimethyl cyclohexanone as a raw material to react with phosphorus tribromide, dichloromethane and N,N-dimethylformamide mixed solution, so 2-bromine-5,5-dimethyl cyclohexyl-1-yl-formaldehyde 2 is generated; step 2, reduction reaction: a compound 2 undergoes the reduction reaction under the action of sodium borohydride to generate the corresponding alcoholate; step 3, bromination reaction: the alcoholate undergoes the bromination reaction under the action of phosphorus tribromide to generate the corresponding bromide; and step 4, the reaction is that: the bromide and 4-(diethylenediamine-1-radical) benzoic acid t-butyl ester are subjected to the substitution reaction to generate the intermediate 4-(4-((2-bromine-5,5-dimethyl cyclohexyl-1-alkenyl) diethylenediamine-1-radical) benzoic acid t-butyl ester, and after the Suzuki reaction of a step 5 and the hydrolysis reaction of a step 6, the corresponding carboxylic acid intermediate is generated.
Description
Technical field
The present invention relates to an anticancer compound molecule ABT-263 Intermediate carboxylic acids's fragment [4-(4-((2-(4-chloro-phenyl-)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) phenylformic acid
]improvement synthetic method.
Background technology
ABT-263 be by Abbott Laboratories (Abbott Laboratories) develop a kind of can the small molecules Bel-2 inhibitor of cell death inducing.Formula 1 retrosynthetic analysis shows that this compound can be formed by three fragment assemblies.For the synthesis of this carboxylic acid fragment, patent disclosed in Abbott Laboratories (US2009/318689 A1) and paper (the J. Med. Chem delivered; 2008; 6902-6915) report the synthetic route formula 2 of this compound, but this route complicated operation, productive rate is lower, and wherein the productive rate of reduction amination only has 38%, and most of intermediate all needs to adopt column chromatography for separation, is not suitable for extensive preparation.The people such as Guangjun Wang report (Synthesis; 2008; 2398 – 2404) for the synthetic route formula 3 of the novelty of this carboxylic acid fragment.But through our experimental study, the compound that discovery the method obtains not is target compound
9, but the compound of double-bond positional isomerization
9A.We improve the route of Abbott Laboratories in test, develop a productive rate high, route simple to operate.
Formula 1:
Formula 2:
Formula 3:
Summary of the invention
The object of the invention is to carry out the improvement of route to the important intermediate carboxylic acid fragment of ABT-263, mainly solve existing synthetic method complicated operation, productive rate is low, the problem that synthesis cost is high.
Technical scheme of the present invention: 4-(4-((2-(4-chloro-phenyl-)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) benzoic synthetic method, comprise the following steps: the first step reaction is with 4,4-dimethylcyclohexanon is raw material, by with phosphorus tribromide, methylene dichloride and N, the reaction of dinethylformamide mixing solutions generates bromo-5, the 5-Dimethylcyclohexyl-1-cyclohexene carboxaldehydes 2 of 2-, former reaction is there is and generates (bromo-5, the 5-Dimethylcyclohexyl-1-alkene of 2-) methyl alcohol 3 in bromo-5, the 5-Dimethylcyclohexyl-1-cyclohexene carboxaldehydes of second step reduction reaction: 2-under the effect of sodium borohydride, 3rd step bromination reaction: (2-bromo-5, 5-Dimethylcyclohexyl-1-alkene) under the effect of phosphorus tribromide, there is bromination reaction generate 1-bromo-2-brooethyl-4 in methyl alcohol, 4-Dimethylcyclohexyl-1-alkene 4, the bromo-2-brooethyl-4 of four-step reaction: 1-, 4-Dimethylcyclohexyl-1-alkene and 4-(piperazine-1-base) t-butyl perbenzoate generation substitution reaction generates intermediate 4-(4-((2-bromo-5, 5-Dimethylcyclohexyl-1-thiazolinyl) piperazine-1-base) t-butyl perbenzoate 6, 5th step Suzuki (Suzuki) is obtained by reacting 4-(4-((2-(4-chloro-phenyl-)-5, 5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) t-butyl perbenzoate
8, the 6th one-step hydrolysis reaction generates corresponding carboxylic acid intermediate 4-(4-((2-(4-chloro-phenyl-) and-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) phenylformic acid 9.
Building-up reactions formula is as follows:
。
In described the first step reaction: the mixing solutions excessive phosphorus tribromide being instilled methylene dichloride and DMF, 4,4-dimethylcyclohexanon
1be dissolved in methylene dichloride, instillation phosphorus tribromide, methylene dichloride and DMF mixing solutions.Be returned to room temperature (20-30 DEG C, rear same) gradually, stir 3-48 hour.
Second step hydrolysis reaction carries out in mixed solvent tetrahydrofuran (THF) and methyl alcohol, the add-on of sodium borohydride is between 0.9-1.1 equivalent (excessive sodium borohydride will cause the generation of side reaction), stirred at ambient temperature 3-48 hour.
3rd step bromination reaction is by (bromo-5, the 5-Dimethylcyclohexyl-1-alkene of 2-) methyl alcohol
3be dissolved in methyl tertiary butyl ether, be cooled to 0 DEG C, add excessive phosphorus tribromide, stirred at ambient temperature 8-48 hour.
Four-step reaction carries out in mix reagent, the charged material weight of compound 4 and compound 5 is than being 1.1:1, (compound 4 too much will cause side reaction) mix reagent is made up of sodium iodide, triethylamine and DMF, at 60-100 DEG C, stir 1-24 hour.
5th step suzuki reaction is by bromo-for 4-(4-((2-5,5-Dimethylcyclohexyl-1-thiazolinyls) piperazine-1-base) t-butyl perbenzoate
6, 4-chlorophenylboronic acid
7, dichloro two triphenyl phosphorus palladium (0.1-0.3 equivalent), aqueous sodium carbonate, is dissolved in by glycol dimethyl ether, water, in the mixed solvent of ethanol composition (if without ethanol, reaction yield is low), at 80-120 DEG C, stirs 3-24 hour.
Six-step process is hydrolyzed to 4-(4-((2-(4-chloro-phenyl-)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) t-butyl perbenzoate
8be dissolved in the mixed solvent of dioxane and dilute hydrochloric acid, at 80 DEG C, stir 3-24 hour.
The invention has the beneficial effects as follows: the synthetic route providing a kind of improvement, can from raw material that is cheap, that be easy to get, productive rate prepares the important intermediate carboxylic acid fragment of a kind of anticancer compound molecule ABT-263 higher.It is all very high that this technique respectively walks productive rate, and the total recovery through six reactions is 31%, is therefore applicable to large-scale industry synthesis.
Embodiment
Following instance contributes to understanding content of the present invention, the present invention includes but be not limited to following related content.
embodiment 1
Bromo-5, the 5-Dimethylcyclohexyl-1-alkene of 1.(2-) formaldehyde
2synthesis
Phosphorus tribromide (140 mL) instills the methylene dichloride (1.0 liters) of ice bath cooling and the mixing solutions of DMF (130mL).This reaction solution stirs 30 minutes at normal temperatures.Be cooled to 0 DEG C, 4,4-dimethylcyclohexanon
1(65 g, 0.51 mol) is dissolved in 500 mL methylene dichloride, instillation reaction solution.Be returned to room temperature gradually, stir 16 hours.After reaction terminates, be poured over by reaction solution in cold saturated sodium bicarbonate aqueous solution, extract three times with methyl tertiary butyl ether, organic phase merges, and with anhydrous sodium sulfate drying, concentrated dryly obtains bromo-5, the 5-Dimethylcyclohexyl-1-cyclohexene carboxaldehydes of product 2-
2(yield: 81%).
Proton nmr spectra
1h-NMR (CDCl
3, 400 MHz): δ 10.02 (s, 1H), 2.73 (t,
j=5.2 Hz, 2H), 2.08 (s, 2H), 1.53 (t,
j=5.2 Hz, 2H), 0.95 (s, 6H).
Bromo-5, the 5-Dimethylcyclohexyl-1-alkene of 2.(2-) methyl alcohol
3synthesis
By (bromo-5, the 5-Dimethylcyclohexyl-1-alkene of 2-) formaldehyde
2(86 g, 0.40 mol) is dissolved in the mixed solvent of tetrahydrofuran (THF) (600 mL) and methyl alcohol (15 mL), is cooled to 0 DEG C, adds sodium borohydride (14.9 g, 0.40 mol), stirred at ambient temperature 16 hours in batches.After reaction terminates, be poured over by reaction solution in frozen water mixed solution, be extracted with ethyl acetate three times, organic phase merges, and with anhydrous sodium sulfate drying, concentrated dryly obtains 88 grams of bromo-5,5-Dimethylcyclohexyl-1-alkene methyl alcohol of product 2-
3(yield: 100%).
Proton nmr spectra
1h-NMR (CDCl
3, 400 MHz): δ 4.20 (s, 2H), 2.53 (t,
j=5.2 Hz, 2H), 2.08 (s, 2H), 1.43 (t,
j=5.2 Hz, 2H), 0.93 (s, 6H).
The synthesis of 3.1-bromo-2-brooethyl-4,4-Dimethylcyclohexyl-1-alkene 4
Bromo-5, the 5-Dimethylcyclohexyl-1-alkene methyl alcohol of 2-
3(45 g, 0.21 mol) is dissolved in 600 mL methyl tertiary butyl ethers, is cooled to 0 DEG C, and phosphorus tribromide (90 mL) instilled in one hour.Stirred at ambient temperature 16 hours.After reaction terminates, be poured over by reaction solution in frozen water mixed solution, be extracted with ethyl acetate three times, organic phase merges, and with anhydrous sodium sulfate drying, concentrated dryly obtains 51 grams of product 1-bromo-2-brooethyl-4,4-Dimethylcyclohexyl-1-alkene
4(yield: 86%).
Proton nmr spectra
1h-NMR (CDCl
3, 400 MHz): δ 4.12 (s, 2H), 2.53 (t,
j=5.2 Hz, 2H), 2.03 (s, 2H), 1.43 (t,
j=5.2 Hz, 2H), 0.93 (s, 6H).
4. bromo-5, the 5-Dimethylcyclohexyl-1-thiazolinyls of 4-(4-((2-) piperazine-1-base) t-butyl perbenzoate
6synthesis
1-bromo-2-brooethyl-4,4-Dimethylcyclohexyl-1-alkene
4(80 g, 0.28 mol), 4-(piperazine-1-base) t-butyl perbenzoate
5(63.2 g, 0.24 mol), sodium iodide (127 g, 0.85 mol), triethylamine (100 mL) joins in 800 milliliters of DMFs, stirs 3 hours at 80 DEG C.After reaction terminates, by reaction solution evaporate to dryness, add 500mL water and 500 mL ethyl acetate, separatory, aqueous phase is extracted with ethyl acetate three times, and organic phase merges, with anhydrous sodium sulfate drying, concentrated dryly obtain 90 grams of bromo-5,5-Dimethylcyclohexyl-1-thiazolinyls of product 4-(4-((2-) piperazine-1-base) t-butyl perbenzoate
6(yield: 70%).
Proton nmr spectra
1h-NMR (CDCl
3, 400 MHz): δ 7.85 (d,
j=8.8 Hz, 2H), 6.82 (d,
j=8.8 Hz, 2H), 3.27 (t,
j=4.8 Hz, 4H), 3.12 (s, 2H), 2.55 (m, 6H), 2.02 (s, 2H), 1.58 (s, 9H), 1.43 (t,
j=6.4 Hz, 2H), 0.93 (s, 6H).
5. 4-(4-((2-(4-chloro-phenyl-)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) t-butyl perbenzoate
8synthesis
By bromo-for 4-(4-((2-5,5-Dimethylcyclohexyl-1-thiazolinyls) piperazine-1-base) t-butyl perbenzoate
6(18.5 g, 40 mmol), 4-chlorophenylboronic acid
7(6.2 g, 40 mmol), dichloro two triphenylphosphine palladium (2.8 g, 4 mmol), aqueous sodium carbonate (2mol L
-1, 24mL), be dissolved in the mixed solvent that 240 mL are made up of (glycol dimethyl ether: water: the volume ratio=15:6:4 of ethanol), stir 3 hours at 80 DEG C.After reaction terminates, reaction solution is poured in frozen water mixed solution, be extracted with ethyl acetate three times, organic phase merges, with anhydrous sodium sulfate drying, concentrated dryly obtain crude product, in dehydrated alcohol, recrystallization obtains 7.0 grams of product 4-(4-((2-(4-chloro-phenyl-s)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) t-butyl perbenzoate
8(yield: 71%).
Proton nmr spectra
1h-NMR (CDCl
3, 400 MHz): δ 7.85 (d,
j=7.2 Hz, 2H), 7.25 (d,
j=8.4 Hz, 2H), 6.98 (d,
j=8.4 Hz, 2H), 6.80 (d,
j=7.2 Hz, 2H), 3.27 (t,
j=4.8 Hz, 4H), 2.78 (s, 2H), 2.35 (t,
j=5.2 Hz, 4H), 2.25 (t,
j=6.4 Hz, 2H), 2.05 (s, 2H), 1.58 (s, 9H), 1.43 (t,
j=6.4 Hz, 2H), 0.97 (s, 6H).
6. 4-(4-((2-(4-chloro-phenyl-)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) phenylformic acid
9synthesis
4-(4-((2-(4-chloro-phenyl-)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) t-butyl perbenzoate
8(5 g, 10 mmol) are dissolved in 50 milliliters of dioxane and 50 milliliters of dilute hydrochloric acid (6mol L
-1) mixed solvent in, at 80 DEG C stir 3 hours.By solvent evaporate to dryness, add 50mL sodium bicarbonate aqueous solution and 50 mL ethyl acetate, separatory, aqueous phase is extracted with ethyl acetate three times, organic phase merges, with anhydrous sodium sulfate drying, concentrated dryly obtain 4 grams of product 4-(4-((2-(4-chloro-phenyl-s)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) phenylformic acid
9(yield: 91%).
Proton nmr spectra
1h-NMR (CDCl
3, 400 MHz): δ 7.94 (d,
j=7.2 Hz, 2H), 7.25 (d,
j=8.4 Hz, 2H), 6.98 (d,
j=8.4 Hz, 2H), 6.80 (d,
j=7.2 Hz, 2H), 3.29 (t,
j=4.8 Hz, 4H), 2.80 (s, 2H), 2.35 (t,
j=5.2 Hz, 4H), 2.25 (t,
j=6.4 Hz, 2H), 2.03 (s, 2H), 1.47 (t,
j=6.4 Hz, 2H), 0.98 (s, 6H).
embodiment 2
Reaction formula is see embodiment 1
Bromo-5, the 5-Dimethylcyclohexyl-1-alkene of 1.(2-) formaldehyde
2synthesis
Phosphorus tribromide (140 mL) instills the methylene dichloride (1.0 liters) of ice bath cooling and the mixing solutions of DMF (130mL).This reaction solution stirs 30 minutes at normal temperatures.Be cooled to 0 DEG C, 4,4-dimethylcyclohexanon
1(65 g, 0.51 mol) is dissolved in 500 mL methylene dichloride, instillation reaction solution.Be returned to room temperature gradually, stir 3 hours.After reaction terminates, be poured over by reaction solution in cold saturated sodium bicarbonate aqueous solution, extract three times with methyl tertiary butyl ether, organic phase merges, and with anhydrous sodium sulfate drying, concentrated dryly obtains bromo-5, the 5-Dimethylcyclohexyl-1-cyclohexene carboxaldehydes of product 2-
2(yield: 75%).
Proton nmr spectra
1h-NMR (CDCl
3, 400 MHz): δ 10.02 (s, 1H), 2.73 (t,
j=5.2 Hz, 2H), 2.08 (s, 2H), 1.53 (t,
j=5.2 Hz, 2H), 0.95 (s, 6H).
Bromo-5, the 5-Dimethylcyclohexyl-1-alkene of 2.(2-) methyl alcohol
3synthesis
By (bromo-5, the 5-Dimethylcyclohexyl-1-alkene of 2-) formaldehyde
2(86 g, 0.40 mol) is dissolved in the mixed solvent of tetrahydrofuran (THF) (600 mL) and methyl alcohol (150 mL), is cooled to 0 DEG C, adds sodium borohydride (14.9 g, 0.40 mol), stirred at ambient temperature 10 hours in batches.After reaction terminates, be poured over by reaction solution in frozen water mixed solution, be extracted with ethyl acetate three times, organic phase merges, and with anhydrous sodium sulfate drying, concentrated dryly obtains bromo-5, the 5-Dimethylcyclohexyl-1-alkene methyl alcohol of product 2-
3(yield: 80%).
Proton nmr spectra
1h-NMR (CDCl
3, 400 MHz): δ 4.20 (s, 2H), 2.53 (t,
j=5.2 Hz, 2H), 2.08 (s, 2H), 1.43 (t,
j=5.2 Hz, 2H), 0.93 (s, 6H).
The synthesis of 3.1-bromo-2-brooethyl-4,4-Dimethylcyclohexyl-1-alkene 4
Bromo-5, the 5-Dimethylcyclohexyl-1-alkene methyl alcohol of 2-
3(45 g, 0.21 mol) is dissolved in 600 mL methyl tertiary butyl ethers, is cooled to 0 DEG C, and phosphorus tribromide (90 mL) instilled in one hour.Stirred at ambient temperature 8 hours.After reaction terminates, be poured over by reaction solution in frozen water mixed solution, be extracted with ethyl acetate three times, organic phase merges, and with anhydrous sodium sulfate drying, concentrated dryly obtains product 1-bromo-2-brooethyl-4,4-Dimethylcyclohexyl-1-alkene
4(yield: 76%).
Proton nmr spectra
1h-NMR (CDCl
3, 400 MHz): δ 4.12 (s, 2H), 2.53 (t,
j=5.2 Hz, 2H), 2.03 (s, 2H), 1.43 (t,
j=5.2 Hz, 2H), 0.93 (s, 6H).
Bromo-5, the 5-Dimethylcyclohexyl-1-thiazolinyls of 4.4-(4-((2-) piperazine-1-base) t-butyl perbenzoate
6synthesis
1-bromo-2-brooethyl-4,4-Dimethylcyclohexyl-1-alkene
4(80 g, 0.28 mol), 4-(piperazine-1-base) t-butyl perbenzoate
5(63.2 g, 0.24 mol), sodium iodide (127 g, 0.85 mol), triethylamine (100 mL) joins in 800 milliliters of DMFs, stirs 24 hours at 80 DEG C.After reaction terminates, by reaction solution evaporate to dryness, add 500mL water and 500 mL ethyl acetate, separatory, aqueous phase is extracted with ethyl acetate three times, and organic phase merges, with anhydrous sodium sulfate drying, concentrated dryly obtain bromo-5, the 5-Dimethylcyclohexyl-1-thiazolinyls of product 4-(4-((2-) piperazine-1-base) t-butyl perbenzoate
6(yield: 73%).
Proton nmr spectra
1h-NMR (CDCl
3, 400 MHz): δ 7.85 (d,
j=8.8 Hz, 2H), 6.82 (d,
j=8.8 Hz, 2H), 3.27 (t,
j=4.8 Hz, 4H), 3.12 (s, 2H), 2.55 (m, 6H), 2.02 (s, 2H), 1.58 (s, 9H), 1.43 (t,
j=6.4 Hz, 2H), 0.93 (s, 6H).
5.4-(4-((2-(4-chloro-phenyl-)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) t-butyl perbenzoate
8synthesis
By bromo-for 4-(4-((2-5,5-Dimethylcyclohexyl-1-thiazolinyls) piperazine-1-base) t-butyl perbenzoate
6(18.5 g, 40 mmol), 4-chlorophenylboronic acid
7(6.2 g, 40 mmol), dichloro two triphenylphosphine palladium (2.8 g, 4 mmol), aqueous sodium carbonate (2mol L
-1, 24mL), be dissolved in the mixed solvent that 240 mL are made up of (glycol dimethyl ether: water: the volume ratio=15:6:4 of ethanol), stir 10 hours at 100 DEG C.After reaction terminates, reaction solution is poured in frozen water mixed solution, be extracted with ethyl acetate three times, organic phase merges, with anhydrous sodium sulfate drying, concentrated dryly obtain crude product, in dehydrated alcohol, recrystallization obtains product 4-(4-((2-(4-chloro-phenyl-)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) t-butyl perbenzoate
8(yield: 75%).
Proton nmr spectra
1h-NMR (CDCl
3, 400 MHz): δ 7.85 (d,
j=7.2 Hz, 2H), 7.25 (d,
j=8.4 Hz, 2H), 6.98 (d,
j=8.4 Hz, 2H), 6.80 (d,
j=7.2 Hz, 2H), 3.27 (t,
j=4.8 Hz, 4H), 2.78 (s, 2H), 2.35 (t,
j=5.2 Hz, 4H), 2.25 (t,
j=6.4 Hz, 2H), 2.05 (s, 2H), 1.58 (s, 9H), 1.43 (t,
j=6.4 Hz, 2H), 0.97 (s, 6H).
6. 4-(4-((2-(4-chloro-phenyl-)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) phenylformic acid
9synthesis
4-(4-((2-(4-chloro-phenyl-)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) t-butyl perbenzoate
8(5 g, 10 mmol) are dissolved in 50 milliliters of dioxane and 50 milliliters of dilute hydrochloric acid (12mol L
-1) mixed solvent in, at 80 DEG C stir 16 hours.By solvent evaporate to dryness, add 50mL sodium bicarbonate aqueous solution and 50 mL ethyl acetate, separatory, aqueous phase is extracted with ethyl acetate three times, organic phase merges, with anhydrous sodium sulfate drying, concentrated dryly obtain product 4-(4-((2-(4-chloro-phenyl-)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) phenylformic acid
9(yield: 95%).
Proton nmr spectra
1h-NMR (CDCl
3, 400 MHz): δ 7.94 (d,
j=7.2 Hz, 2H), 7.25 (d,
j=8.4 Hz, 2H), 6.98 (d,
j=8.4 Hz, 2H), 6.80 (d,
j=7.2 Hz, 2H), 3.29 (t,
j=4.8 Hz, 4H), 2.80 (s, 2H), 2.35 (t,
j=5.2 Hz, 4H), 2.25 (t,
j=6.4 Hz, 2H), 2.03 (s, 2H), 1.47 (t,
j=6.4 Hz, 2H), 0.98 (s, 6H).
Claims (1)
1.4-(4-((2-(4-chloro-phenyl-)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) benzoic synthetic method, comprise the following steps: the first step is reacted with 4,4-dimethylcyclohexanon for raw material, by 4,4-dimethylcyclohexanon is dissolved in methylene dichloride, instill phosphorus tribromide, methylene dichloride and DMF mixing solutions again, be returned to room temperature gradually, stir and generate bromo-5, the 5-Dimethylcyclohexyl-1-cyclohexene carboxaldehydes of 2-in 3-48 hour, second step reduction reaction is carried out in mixed solvent tetrahydrofuran (THF) and methyl alcohol: 2-bromo-5,5-Dimethylcyclohexyl-1-cyclohexene carboxaldehyde issues raw reduction reaction in the effect of sodium borohydride and generates (2-bromo-5,5-Dimethylcyclohexyl-1-alkene) methyl alcohol, the add-on of sodium borohydride is 0.9-1.1 equivalent, stirred at ambient temperature 3-48 hour, 3rd step bromination reaction: by (2-bromo-5, 5-Dimethylcyclohexyl-1-alkene) dissolve with methanol is in methyl tertiary butyl ether, be cooled to 0 DEG C, add excessive phosphorus tribromide, within stirred at ambient temperature 8-48 hour, generate the bromo-2-brooethyl-4 of 1-, 4-Dimethylcyclohexyl-1-alkene, the bromo-2-brooethyl-4 of four-step reaction: 1-, 4-Dimethylcyclohexyl-1-alkene and 4-(piperazine-1-base) t-butyl perbenzoate generation substitution reaction generates intermediate 4-(4-((2-bromo-5, 5-Dimethylcyclohexyl-1-thiazolinyl) piperazine-1-base) t-butyl perbenzoate, four-step reaction carries out in mix reagent, mix reagent is by sodium iodide, triethylamine and N, dinethylformamide is formed, 1-24 hour is stirred at 60-100 DEG C, the bromo-2-brooethyl-4 of 1-, 4-Dimethylcyclohexyl-1-alkene and 4-(piperazine-1-base) t-butyl perbenzoate charged material weight is than for 1.1:1, 5th step suzuki reaction: by bromo-for 4-(4-((2-5,5-Dimethylcyclohexyl-1-thiazolinyl) piperazine-1-base) t-butyl perbenzoate, 4-chlorophenylboronic acid, dichloro two triphenyl phosphorus palladium and aqueous sodium carbonate be dissolved in the mixed solvent be made up of glycol dimethyl ether, water and ethanol, stir at 80-120 DEG C and obtain 4-(4-((2-(4-chloro-phenyl-in 3-24 hour)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) t-butyl perbenzoate, glycol dimethyl ether: water: the volume ratio=15:6:4 of ethanol, 6th one-step hydrolysis reaction: by 4-(4-((2-(4-chloro-phenyl-)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) t-butyl perbenzoate is dissolved in the mixed solvent of dioxane and dilute hydrochloric acid, stir at 80 DEG C and within 3-24 hour, generate corresponding carboxylic acid intermediate 4-(4-((2-(4-chloro-phenyl-)-5,5-Dimethylcyclohexyl-1-alkene) methyl) piperazine-1-base) phenylformic acid.
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