CN113979881A - Synthesis of side-chain fully-deuterated D17Method for preparing (S) -acebutolol - Google Patents

Synthesis of side-chain fully-deuterated D17Method for preparing (S) -acebutolol Download PDF

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CN113979881A
CN113979881A CN202111358053.7A CN202111358053A CN113979881A CN 113979881 A CN113979881 A CN 113979881A CN 202111358053 A CN202111358053 A CN 202111358053A CN 113979881 A CN113979881 A CN 113979881A
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deuterated
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acebutolol
aminophenol
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赵嘉
盛瑞隆
姜珍华
徐涛
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Shandong Shenganbei New Energy Co ltd Nanjing Branch
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    • C—CHEMISTRY; METALLURGY
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Abstract

The invention belongs to the field of nonradioactive isotope pharmaceutical chemistry, and particularly relates to a method for synthesizing side chain fully deuterated D17A method of (S) -acebutolol. P-aminophenol and D7Mixing deuterated n-butyric anhydride, carrying out water diversion reaction,cooling, dispersing, adding alkali to generate phenolate, adding D3Reacting deuterated acetic anhydride to generate ester, and separating to obtain an intermediate I; dissolving the intermediate I in an organic solvent, carrying out Fries rearrangement in a microwave reactor, and after the reaction is finished, hydrolyzing, extracting and separating to obtain an intermediate II; condensing (S) -epichlorohydrin with the phenolate of the intermediate II, filtering and recrystallizing after the reaction is finished, and preparing an intermediate III; dissolving the intermediate III in an organic solvent to directly react with D7Reacting with deuterated isopropylamine, separating and purifying to obtain side chain fully deuterated D17- (S) -acebutolol. The method of the invention uses low-toxicity, high-efficiency and economic chemical reagents in the synthesis process, and is an atom-economic synthesis method.

Description

Synthesis of side-chain fully-deuterated D17Method for preparing (S) -acebutolol
Technical Field
The invention belongs to the field of nonradioactive isotope pharmaceutical chemistry, and particularly relates to a method for synthesizing side chain fully deuterated D17A method of (S) -acebutolol.
Background
The drug metabolism rate is greatly influenced by chemical bonds, and the stability of the C-D chemical bond of carbon deuterium is 6-9 times higher than that of the C-H chemical bond of carbon due to the isotope effect, so that the research on the deuterated isotope analogues of the traditional marketed drugs can deeply understand the metabolic mechanism of the drugs, improve the metabolic stability, improve the active metabolites and reduce the formation of side metabolites. In general, deuterated drugs can retain biochemical activity similar to hydrogenated drugs. The effect of deuterium substitution on metabolic properties is highly dependent on the number of deuterations and the position of the deuteration. Compared with corresponding hydrogenated drugs, some deuterated drugs have prolonged half-life in vivo, and can improve the safety, effectiveness, tolerance and long-circulating property of the drugs. Can help develop isotope drugs with higher efficiency and lower cost. 5 months in 2020, first deuterated drug Austedo
Figure BSA0000257900690000011
And the method provides a wide prospect for the research and development of deuterated drugs and intermediates. Under the background of rapid development of international isotope biochemical drugs, the research on deuterated drugs is accelerated, and the method has extremely important scientific and technological significance and market prospects for forming deuterated drugs and intermediate production and study systems with independent intellectual property rights in China.
(S) -acebutolol is a common cardiovascular drug (beta receptor blocker) with beta 1-adrenergic receptor selectivity, and can be used for treating hypertension, arrhythmia, myocardial infarction and other diseases. Synthesis of deuterated- (S) -acebutolol and important intermediate 2-D thereof as non-radioisotope bioisostere analogue of beta-receptor blocker- (S) -acebutolol3-deuterated acetyl-4-D7The deuterated n-butylaminophenol has important economic and social values for developing a synthetic route thereof.
Regarding the synthesis of the common (S) -acebutolol and the intermediate 2-acetyl-4-n-butylamidophenol thereof, relevant reports are provided on U.S. Pat. Nos. 3726919, 3857952 and 3928601, and relevant solid-phase solvent-free synthesis methods are also reported in the application of Chinese patent CN1970529A, but simple synthesis methods of deuterated (S) -acebutolol are not reported yet.
Disclosure of Invention
The invention aims to fill the blank field in the prior isotope medicament technology, uses a reagent with lower cost, has simpler reaction operation, combines an environment-friendly and green chemical synthesis method to synthesize the non-radioactive isotope bioisostere of the beta receptor blocker- (S) -acebutolol: side chain fully deuterated D17- (S) -acebutolol.
The method is carried out under mild reaction conditions without a high-temperature high-pressure device, and uses the following steps: 1. has atom economical continuous reaction (Tandem reaction) synthesis method, 2. microwave chemical Fries rearrangement reaction, and the used reagent has the advantages of small dosage, low toxicity and lower cost.
In order to realize the purpose, the invention discloses a method for synthesizing side chain fully deuterated D17A method of (S) -acebutolol comprising the steps of:
the method comprises the following steps: p-aminophenol and D7-deuterated n-butyric anhydride; refluxing with organic solvent, cooling, adding dispersant, adding base to react to obtain phenolate, adding D3-deuterated acetic anhydride to react to obtain deuterated acetate, and separating to obtain intermediate I N- (4-D)3-deuterated acetoxyphenyl) -D7-deuterated n-butylamide;
step two: microwave irradiating intermediate I and aluminum trichloride in microwave reactor to perform Fries rearrangement reaction, hydrolyzing, extracting, separating to obtain intermediate II2-D3-deuterated acetyl-4-D7-deuterated n-butylaminophenol;
step three: condensing (S) -epichlorohydrin with the phenolate aqueous solution of the intermediate IIFiltering and recrystallizing to obtain an intermediate III (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3-deuterated acetophenone;
step four: dissolving intermediate III in organic solvent, adding D7Reaction of deuterated isopropylamine, removal of the solvent and excess D by distillation under reduced pressure7Separating to obtain final product with side chain being fully deuterated D17- (S) -acebutolol.
Preferably, the method comprises the following steps: in step one, p-aminophenol and D7The mol ratio of the-deuterated n-butyric anhydride is 1: 3-1: 6; p-aminophenol and D3The mol ratio of the-deuterated acetic anhydride is 1: 2-1: 4, and the preferable mol ratio is 1: 1.5. P-aminophenol and D7The molar ratio of the deuterated n-butyric anhydride enables the reaction to be more complete and the yield to be higher, and simultaneously saves raw materials. P-aminophenol and D3The mol ratio of the-deuterated acetic anhydride is 1: 2-1: 4, preferably 1: 1.5, so that the yield is higher.
Preferably, the method comprises the following steps: in the first step, toluene is used as an organic solvent for reflux, and deionized water is used as a dispersing agent; the alkali is sodium hydroxide with a molar ratio of 1.5 times. The toluene is used as a solvent, on one hand, the toluene raw material is easy to obtain, the cost is low, and meanwhile, the toluene can be removed by adopting a normal pressure distillation mode after the subsequent reaction is finished, so that the method is efficient, energy-saving, cost-saving and green in production. And the reflux reaction temperature is lower than that of other solvents, so that the yield is high, and toluene is preferably used as the reflux reaction solvent in the invention.
Preferably, the method comprises the following steps: in the second step, the microwave irradiation time with the rated power consumption of 1100W is 0.5-4 h, preferably 2 h. The microwave reactor has high reaction speed, can synthesize substances which are difficult to produce by the conventional method, and adopts microwave irradiation with the rated consumption power of 1100W in the step, so that the reaction speed is accelerated, and the yield is improved.
Preferably, the method comprises the following steps: and in the second step, deionized water is added for hydrolysis in the hydrolysis process, ethyl acetate is used for extraction in the extraction process, and the solvent is heated and evaporated after the extraction is finished. Deionized water is pure water from which impurities in the form of ions are removed, so that the interference of the impurities on an experiment is reduced, ethyl acetate is used as an extracting agent, the extraction effect is good, the recycling is convenient, and meanwhile, in the synthetic route, the extraction effect of the ethyl acetate on the intermediate is very obvious.
Preferably, the method comprises the following steps: in the second step, (S) -epichlorohydrin and 2-D3-deuterated acetyl-4-D7The molar ratio of the-deuterated n-butylaminophenol is 1: 1-3: 1, and the preferred molar ratio is 2: 1. (S) -Epichlorohydrin and 2-D of the invention3-deuterated acetyl-4-D7The choice of the molar ratio of deuterated n-butylaminophenol leads to higher yields.
Preferably, the method comprises the following steps: step three, 2-D3-deuterated acetyl-4-D7The preparation method of the phenolate of the deuterium-substituted n-butylaminophenol comprises the following steps: 2-D3-deuterated acetyl-4-D7Reacting deuterium n-butylamidophenol with sodium hydroxide according to a molar ratio of 1: 2 to generate phenolate. Sodium hydroxide is preferred because it is inexpensive and widely available. Simultaneous 2-D3-deuterated acetyl-4-D7The deuterated n-butylamidophenol and sodium hydroxide react according to the molar ratio of 1: 2, and the yield is high.
Preferably, the method comprises the following steps: in the third step, the recrystallization solvent is toluene. The toluene is low in price, is a common solvent, has high solubility to a substance to be crystallized near a boiling point and low solubility at a low temperature, and is selected as a recrystallization solvent, so that the recrystallization effect is good.
Preferably, the method comprises the following steps: in step four, D7Deuterated isopropylamine and (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3The mol ratio of the-deuterated acetophenone is 1: 1-2: 1, preferably 1: 1.5. The preferred molar ratio results in a high yield of the synthesis reaction.
Preferably, the method comprises the following steps: step four, (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3The organic solvent in which the deuterated acetophenone is dissolved is tetrahydrofuran or 1, 4-dioxane. Tetrahydrofuran is cheap and has low boiling point, so that the cost is saved. Both 1, 4-dioxane and tetrahydrofuran can be used as polar aprotic solvents.
Preferably, in step one, the silica gel column is separated (eluent n-hexane: ethyl acetate)1: 5) to obtain an intermediate N- (4-D)3-deuterated acetoxyphenyl) -D7Deuterated n-butylamide. The silica gel column has good separation effect.
Preferably, in step two, silica gel column separation (eluent n-hexane: ethyl acetate 3: 1) provides important intermediate 2-D of deuterated acebutolol as intermediate3-deuterated acetyl-4-D7-deuterated n-butylaminophenol. The silica gel column has good separation effect.
Preferably, in step four, silica gel column separation (eluent chloroform: methanol ═ 3: 1) gives the final product side chain deuterated D17- (S) -acebutolol. The silica gel column has good separation effect.
Preferably, in step one, p-aminophenol and D7The reflux reaction time of the deuterated n-butyric anhydride is 12 hours.
Preferably, in step one, p-aminophenol and D3And (4) stirring the-deuterated acetic anhydride to react for 4 hours to generate ester.
Preferably, in step three, (S) -epichlorohydrin and intermediate III2-D3-deuterated acetyl-4-D7-condensation reaction of deuterated n-butylamidophenol with aqueous phenoxide solution for 24 h.
Preferably, in the fourth step, the reaction time is 2-10 h, preferably 4 h.
Compared with the prior art, the side chain of the invention is fully deuterated D17The synthesis method of the- (S) -acebutolol has the following advantages:
1. the synthesis method is simple and easy to operate, the reaction is carried out under mild reaction conditions, and an atom-economical continuous reaction (Tandem reaction) synthesis method and a microwave chemical Fries rearrangement reaction are used.
2. The invention uses low-toxicity, low-pollution and cheap green chemical reagents in the synthesis process, does not need high temperature and high pressure, and the side chain of the reaction product is fully deuterated D17The post-treatment process of the- (S) -acebutolol and the intermediate is environment-friendly, and the purification operation is conventional and convenient.
3. The synthesis method can achieve the milligram-level preparation in a laboratory and can realize large-scale industrial production, and a chemical synthesis method with development prospect is provided for further developing the synthesis of other deuterated beta-receptor blockers and intermediates thereof.
Detailed Description
The present invention is further illustrated by the following examples.
Synthesis of side chain fully deuterated D in the invention17The four-step reaction of- (S) -acebutolol is as follows:
the first step of reaction: synthesis of intermediate I N- (4-D)3-deuterated acetoxyphenyl) -D7Deuterated n-butylamides
Figure BSA0000257900690000041
P-aminophenol and D7-deuterated n-butyric anhydride; reflux reacting with organic solvent, cooling, adding dispersant, adding sodium hydroxide to react to obtain phenolate, and adding D3Deuterated acetic anhydride, reacting to generate ester, and separating to obtain intermediate I N- (4-D)3-deuterated acetoxyphenyl) -D7Deuterated n-butylamide.
The second step of reaction: synthesis of intermediate II2-D by microwave chemical Fries rearrangement reaction3-deuterated acetyl-4-D7-deuterated n-butylaminophenol
Figure BSA0000257900690000042
Aluminium trichloride and intermediate IN- (4-D)3-deuterated acetoxyphenyl) -D7Subjecting deuterated n-butylamide to 1000W (1100W can also be used) microwave irradiation in a microwave reactor, hydrolyzing, extracting, and separating to obtain intermediate II2-D3-deuterated acetyl-4-D7-deuterated n-butylaminophenol.
The third step of reaction: synthesis of intermediate III (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3-deuterated acetophenones
Figure BSA0000257900690000043
Mixing (S) -epichlorohydrin with intermediate II2-D3-deuterated acetyl-4-D7Carrying out condensation reaction on a phenate aqueous solution of deuterated n-butylamidophenol, filtering and recrystallizing to obtain an intermediate III (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3-deuterated acetophenone.
And a fourth step of reaction: synthesis of side chain fully deuterated D17- (S) -acebutolol
Figure BSA0000257900690000044
Intermediate III (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3Dissolving deuterated acetophenone in organic solvent, adding D7Reaction of deuterated isopropylamine, removal of the solvent and excess D by distillation under reduced pressure7Separating to obtain final product with side chain being fully deuterated D17- (S) -acebutolol.
In the invention, a high-efficiency continuous deuteration acylation synthesis method is adopted in the first step, raw materials of p-aminophenol and D7-deuteration N-butylanhydride are mixed, water division reaction is carried out by using organic solvents such as toluene and the like, then the organic solvents are distilled off, the reactant is cooled, deionized water is added as a dispersing agent, then sodium hydroxide is added for reaction to generate phenate, D3-deuteration acetic anhydride is dropwise added and then stirred for reaction to generate deuteration acetate, and the product N- (4-D3-deuteration acetoxy phenyl) -D7-deuteration N-butylamide in the first step is obtained through silica gel column separation. And in the second step, microwave chemical Fries rearrangement reaction is adopted, the product in the first step is dissolved in an organic solvent, Fries rearrangement is carried out in a microwave reactor, deionized water is added for hydrolysis after the reaction is finished, the organic solvent is extracted, and silica gel column separation is carried out to obtain the important intermediate 2-D3-deuterated acetyl-4-D7-deuterated n-butylamidophenol of deuterated acebutolol. And step three, condensing (S) -epichlorohydrin with the phenolate of the product of the step two, filtering and recrystallizing after the reaction is finished, and preparing the (S) -5-D7-deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3-deuterated acetophenone. And finally, dissolving the product obtained in the third step in an organic solvent to directly react with D7-deuterated isopropylamine, and separating and purifying to obtain the side chain fully-deuterated D17- (S) -acebutolol.
Example 1
The first step of reaction: synthesis of intermediate I N- (4-D)3-deuterated acetoxyphenyl) -D7Deuterated n-butylamides
Figure BSA0000257900690000051
Charging D into the reactor7Deuterated n-butyric anhydride (4.30g, 0.025mol) and p-aminophenol (1.10g, 0.01mol), wherein p-aminophenol is reacted with D7-deuterated n-butyric anhydride in a molar ratio of 1: 2.5; refluxing and reacting 30mL of toluene for 12h, and distilling to remove toluene and excessive D under normal pressure7Deuterium n-butyric anhydride, cooling the reactant, adding 50mL of deionized water as a dispersing agent, stirring and dropwise adding sodium hydroxide with the molar ratio of 1.5 times to react to generate phenolate, and then dropwise adding D3Deuterated acetic anhydride (1.62g, 0.015mol), of which p-aminophenol is reacted with D3The molar ratio of the-deuterated acetic anhydride is 1: 1.5; stirring for reaction for 4h to generate ester, separating with silica gel column (eluent n-hexane: ethyl acetate: 5: 1) to obtain intermediate IN- (4-D)3-deuterated acetoxyphenyl) -D7Deuterated n-butylamide (1.89g, 0.0082mol), yield 82%.
The second step of reaction: synthesis of intermediate II2-D by microwave chemical Fries rearrangement reaction3-deuterated acetyl-4-D7-deuterated n-butylaminophenol
Figure BSA0000257900690000061
The product of the first step, N- (4-D)3-deuterated acetoxyphenyl) -D7Deuterated N-butylamide (1.89g, 0.0082mol), charging into a reaction vessel and adding aluminum trichloride (2.20g, 0.017mol), wherein the aluminum trichloride and N- (4-D)3-deuterated acetoxyphenyl) -D7The mol ratio of the-deuterated n-butylamide is 2: 1, and the mixture is placed in a microwave reactorIrradiating with microwave with rated power consumption of 1100W for 2.0h, hydrolyzing with 100mL deionized water, extracting with ethyl acetate, heating to evaporate ethyl acetate, separating with silica gel column (eluent n-hexane: ethyl acetate: 3: 1) to obtain important intermediate 2-D of deuterated acebutolol3-deuterated acetyl-4-D7Deuterated n-butylamidophenol (1.17g, 0.0051mol), yield 62%.
The third step of reaction: synthesis of intermediate III (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3-deuterated acetophenones
Figure BSA0000257900690000062
Mixing (S) -epichlorohydrin (0.93g, 0.01mol) with the second step product 2-D3-deuterated acetyl-4-D7An aqueous solution of phenolate (prepared by adding sodium hydroxide in a molar ratio of 1: 2) of deuterated n-butylaminophenol (1.17g, 0.0051mol) was condensed for 24h with (S) -epichlorohydrin and the second product, 2-D3-deuterated acetyl-4-D7The molar ratio of the (E) -deuterated n-butylaminophenol is 2: 1, and after the reaction is finished, the mixture is filtered and recrystallized by acetone to prepare the (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3Deuterated acetophenone (1.09g, 0.0037mol), yield 74%.
And a fourth step of reaction: synthesis of side chain fully deuterated D17- (S) -acebutolol
Figure BSA0000257900690000063
The product (S) -5-D obtained in the third step7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3Deuterated acetophenone (3.27g, 0.0108mol) was dissolved in 30mL tetrahydrofuran, and D was added7Deuterated isopropylamine (0.50g, 0.0072mol) for 4h, in which D is7Deuterated isopropylamine and (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3The mol ratio of the-deuterated acetophenone is 1: 1.5, and after the reaction is finished, the mixture is subjected to reduced pressure distillationRemoval of tetrahydrofuran and excess D7Deuterated isopropylamine, then separated on silica gel (eluent chloroform: methanol 3: 1) to obtain the final product side chain fully deuterated D17- (S) -acebutolol (2.11g, 0.0059mol), yield 82%.
Example 2
The first step of reaction: synthesis of intermediate IN- (4-D)3-deuterated acetoxyphenyl) -D7Deuterated n-butylamides
Figure BSA0000257900690000071
Charging D into the reactor7Deuterated n-butyric anhydride (5.16g, 0.03mol) and p-aminophenol (1.10g, 0.01mol), wherein p-aminophenol is reacted with D7-deuterated n-butyric anhydride in a molar ratio of 1: 3; refluxing and reacting with 20mL of toluene for 12h, and distilling off the toluene and excessive D under normal pressure7Deuterium n-butyric anhydride, cooling the reactant, adding 40mL of deionized water as a dispersing agent, stirring and dropwise adding sodium hydroxide with the molar ratio of 1.5 times to react to generate phenolate, and then dropwise adding D3Deuterated acetic anhydride (2.16g, 0.02mol), of which p-aminophenol is reacted with D3The molar ratio of the-deuterated acetic anhydride is 1: 2; stirring for reaction for 4h to generate ester, and separating with silica gel column (eluent N-hexane: ethyl acetate: 5: 1) to obtain N- (4-D)3-deuterated acetoxyphenyl) -D7Deuterated n-butylamide (1.75g, 0.0076mol), yield 76%.
The second step of reaction: synthesis of 2-D by microwave chemical Fries rearrangement reaction3-deuterated acetyl-4-D7-deuterated n-butylaminophenol
Figure BSA0000257900690000072
The product of the first step, N- (4-D)3-deuterated acetoxyphenyl) -D7Deuterated N-butylamide (1.75g, 0.0076mol), and aluminum trichloride (2.02g, 0.015mol) was added to the reaction vessel, wherein the aluminum trichloride was reacted with N- (4-D)3-deuterated acetoxyphenyl) -D7-deuterated n-butyrylThe molar ratio of amine is 2: 1, microwave irradiation with rated consumption power of 1100W is adopted in a microwave reactor for 2.0h, 100mL of deionized water is added for hydrolysis, ethyl acetate is used for extraction, heating and evaporating ethyl acetate, then silica gel column separation is carried out (eluent n-hexane and ethyl acetate are 3: 1), and the important intermediate 2-D of the deuterated acebutolol is obtained3-deuterated acetyl-4-D7Deuterated n-butylaminophenol (1.06g, 0.0046mol) in 61% yield.
The third step of reaction: synthesis of (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3-deuterated acetophenones
Figure BSA0000257900690000073
Mixing (S) -epichlorohydrin (1.30g, 0.014mol) with the second step product 2-D3-deuterated acetyl-4-D7Condensation of aqueous solution of phenolate (prepared with sodium hydroxide in a molar ratio of 1: 2) of deuterated n-butylaminophenol (1.06g, 0.0046mol) for 24h with (S) -epichlorohydrin and the second product, 2-D3-deuterated acetyl-4-D7The mol ratio of the (E) -deuterated n-butylaminophenol is 3: 1, after the reaction is finished, the obtained product is filtered and recrystallized by acetone to obtain (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3Deuterated acetophenone (1.09g, 0.0037mol), yield 74%.
And a fourth step of reaction: synthesis of side chain fully deuterated D17- (S) -acebutolol
Figure BSA0000257900690000081
The product (S) -5-D obtained in the third step7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3Deuterated acetophenone (1.09g, 0.0037mo1) was dissolved in 30mL of tetrahydrofuran, and D was added7Deuterated isopropylamine (0.53g, 0.0074mol) for 2h, wherein D7Deuterated isopropylamine and (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3-deuterated acetophenone in a molar ratio of2: 1, after the reaction is finished, removing tetrahydrofuran and excessive D by reduced pressure distillation7Deuterated isopropylamine, then separated on silica gel (eluent chloroform: methanol 3: 1) to obtain the final product side chain fully deuterated D17- (S) -acebutolol (1.06g, 0.0029mol), yield 79%.
Example 3
The first step of reaction: synthesis of N- (4-D)3-deuterated acetoxyphenyl) -D7Deuterated n-butylamides
Figure BSA0000257900690000082
Charging D into the reactor7Deuterated n-butyric anhydride (103.2g, 0.6mol) and p-aminophenol (11.0g, 0.1mol), wherein p-aminophenol is reacted with D7-deuterated n-butyric anhydride in a molar ratio of 1: 6; refluxing and reacting with 20mL of toluene for 12h, and distilling off the toluene and excessive D under normal pressure7Deuterium n-butyric anhydride, cooling the reactant, adding 300mL of deionized water as a dispersing agent, stirring and dropwise adding sodium hydroxide with the molar ratio of 1.5 times to react to generate phenolate, and then dropwise adding D3Deuterated acetic anhydride (43.2g, 0.2mol), from which p-aminophenol is reacted with D3The molar ratio of the-deuterated acetic anhydride is 1: 4; stirring for reaction for 4h to generate ester, and separating with silica gel column (eluent N-hexane: ethyl acetate: 5: 1) to obtain N- (4-D)3-deuterated acetoxyphenyl) -D7Deuterated n-butylamide (11.8g, 0.067mol), 67% yield.
The second step of reaction: synthesis of 2-D by microwave chemical Fries rearrangement reaction3-deuterated acetyl-4-D7-deuterated n-butylaminophenol
Figure BSA0000257900690000091
The product of the first step, N- (4-D)3-deuterated acetoxyphenyl) -D7Deuterated N-butylamide (11.8g, 0.067mol), charging into a reaction vessel and adding aluminum trichloride (26.8g, 0.201mol), wherein the aluminum trichloride and N- (4-D)3-deuterated acetoxyphenyl) -D7The mol ratio of the deuterated n-butylamide is 3: 1, microwave irradiation with the rated consumption power of 1100W is adopted in a microwave reactor for 2.0h, 400mL of deionized water is added for hydrolysis, then ethyl acetate is used for extraction, heating and evaporating ethyl acetate, and then silica gel column separation is carried out (eluent n-hexane and ethyl acetate are 3: 1), thus obtaining the important intermediate 2-D of the deuterated acebutolol3-deuterated acetyl-4-D7Deuterated n-butylaminophenol (8.1g, 0.045mol), yield 68%.
The third step of reaction: synthesis of (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3-deuterated acetophenones
Figure BSA0000257900690000092
Mixing (S) -epichlorohydrin (4.2g, 0.045mol) with the second step product 2-D3-deuterated acetyl-4-D7Condensation of aqueous solution of phenolate (prepared by adding sodium hydroxide in a molar ratio of 1: 2) of deuterated n-butylaminophenol (8.1g, 0.045mol) for 24h with (S) -epichlorohydrin and the second product 2-D3-deuterated acetyl-4-D7The molar ratio of the (E) -deuterated n-butylaminophenol is 1: 1, and after the reaction is finished, the mixture is filtered and recrystallized by acetone to prepare the (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3Deuterated acetophenone (9.9g, 0.034mol), yield 75%.
And a fourth step of reaction: synthesis of side chain fully deuterated D17- (S) -acebutolol
Figure BSA0000257900690000093
The product (S) -5-D obtained in the third step7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3Deuterated acetophenone (9.9g, 0.034mol) was dissolved in 30mL of 1, 4-dioxane, and D was added7Deuterated isopropylamine (2.3g, 0.034mol) for a time wherein D7Deuterated isopropylamine and (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3The mol ratio of the-deuterated acetophenone is 1: 1, and after the reaction is finished, the 1, 4-dioxane and the excessive D are removed by reduced pressure distillation7Deuterated isopropylamine, then separated on silica gel (eluent chloroform: methanol 3: 1) to obtain the final product side chain fully deuterated D17- (S) -acebutolol (9.7g, 0.027mol), yield 78%.
Example 4
Example 1 preparation to give side chain fully deuterated D17The structure of the- (S) -acebutolol is characterized as follows:
m.p.123.2-127.8℃
1H NMR(CDCl3，400MHz，δppm)：9.9(s，1H，CONH，)，8.24(m，1H)，7.27(d，J＝7.6Hz，1H，ArH)，7.08(d，J＝7.4Hz，1H，ArH)，4.21(m，2H，ArO-CH2)，3.90(m，1H，CH)，2.62(d，J＝5.1Hz，2H，CH2NH)，2.10(b，1H，NH)，
13C NMR(CDCl3，100MHz，δppm)195.5，167.9，156.7，131.9，126.2，120.1，118.8，116.9，73.9，69.1，49.5，22.9，22.1，18.9，13.3，12.9
MALDI-TOF-MS：321.45；Calculated：321.50.
the above is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.

Claims (10)

1. Synthesis of side-chain fully-deuterated D17-a process of (S) -acebutolol characterized by the steps of:
the method comprises the following steps: p-aminophenol and D7-deuterated n-butyric anhydride; reflux-reacting with organic solvent, cooling, adding dispersant, adding base to react to obtain phenolate, adding D3-deuterated acetic anhydride to react to obtain deuterated acetate, and separating to obtain intermediate IN- (4-D)3-deuterated acetoxyphenyl) -D7-deuterated n-butylamide;
step two: reacting the intermediate I with aluminum trichloride inMicrowave irradiation in a microwave reactor to perform Fries rearrangement reaction, hydrolysis, extraction and separation to obtain intermediate II2-D3-deuterated acetyl-4-D7-deuterated n-butylaminophenol;
step three: carrying out condensation reaction on (S) -epichlorohydrin and the phenate aqueous solution of the intermediate II, filtering and recrystallizing to prepare an intermediate III (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3-deuterated acetophenone;
step four: dissolving intermediate III in organic solvent, adding D7Reaction of deuterated isopropylamine, removal of the solvent and excess D by distillation under reduced pressure7Separating to obtain final product with side chain being fully deuterated D17- (S) -acebutolol.
2. The method of claim 1, further comprising: in step one, p-aminophenol and D7The mol ratio of the-deuterated n-butyric anhydride is 1: 3-1: 6; p-aminophenol and D3The mol ratio of the-deuterated acetic anhydride is 1: 2-1: 4.
3. The method of claim 1, further comprising: in the first step, the organic solvent is toluene, and the dispersing agent is deionized water; the alkali is sodium hydroxide, wherein the molar ratio of the p-aminophenol to the sodium hydroxide is 1: 1.5.
4. The method of claim 1, further comprising: in the second step, the conditions for carrying out Fries rearrangement reaction by microwave irradiation in the microwave reactor are as follows: the microwave irradiation time with the rated power consumption of 1100W is 0.5-4 h.
5. The method of claim 1, further comprising: and in the second step, deionized water is added for hydrolysis, ethyl acetate is used for extraction, and the ethyl acetate is heated and evaporated after the extraction is finished.
6. The method of claim 1, further comprising: in the third step, (S) -epichlorohydrin and 2-D3-deuterated acetyl-4-D7The molar ratio of the-deuterated n-butylaminophenol is 1: 1-3: 1.
7. The method of claim 1, further comprising: step three, 2-D3-deuterated acetyl-4-D7The preparation method of the phenolate of the deuterium-substituted n-butylaminophenol comprises the following steps: 2-D3-deuterated acetyl-4-D7Reacting deuterium n-butylamidophenol with sodium hydroxide according to a molar ratio of 1: 2 to generate phenolate.
8. The method of claim 1, further comprising: in the third step, the recrystallization solvent is toluene.
9. The method of claim 1, further comprising: in step four, D7Deuterated isopropylamine and (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3The mol ratio of the-deuterated acetophenone is 1: 1-2: 1.
10. The method of claim 1, further comprising: step four, (S) -5-D7Deuterated n-butylamido-2- (2, 3-epoxypropoxy) -D3The organic solvent in which the deuterated acetophenone is dissolved is tetrahydrofuran or 1, 4-dioxane.
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