CN106946650A - A kind of hydrochloric acid A Lei replaces the synthetic method of Buddhist nun's intermediate - Google Patents
A kind of hydrochloric acid A Lei replaces the synthetic method of Buddhist nun's intermediate Download PDFInfo
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- CN106946650A CN106946650A CN201710118823.8A CN201710118823A CN106946650A CN 106946650 A CN106946650 A CN 106946650A CN 201710118823 A CN201710118823 A CN 201710118823A CN 106946650 A CN106946650 A CN 106946650A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/27—Preparation of carboxylic acid esters from ortho-esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses the synthetic method that a kind of hydrochloric acid A Lei replaces Buddhist nun's intermediate, 1)Using the methylpropanoic acid of 2 bromine 2 as initiation material, add thionyl chloride progress chlorination reaction and obtain compound 1;2)To step 1)Ethylo benzene is added in the compound 1 of gained, and adds aluminum trichloride (anhydrous) as catalyst, substitution reaction obtains compound 2;3)By step 2)The compound 2 of gained is dissolved in organic solvent, adds HC (OMe)3, and catalyst zinc chloride is added, it is heated to reflux to reaction completely, rearrangement reaction obtains compound 3;By step 3)The compound 3 of gained is dissolved in organic solvent, adds iodine, adds acid iodide catalytic reaction, generates compound 4;5)In the basic conditions, compound 4 is hydrolyzed, obtains target product hydrochloric acid A Lei for Buddhist nun's intermediate.This synthetic method, simple to operate, high income, cost is lower.
Description
Technical field
The present invention relates to the synthetic method that a kind of hydrochloric acid A Lei replaces Buddhist nun's intermediate.
Background technology
Hydrochloric acid A Lei is used to treat late period the positive non-small cell lung cancers of (metastatic) ALK for Buddhist nun, it is adaptable to controlled through another
Treat the patient for deteriorating or not being resistant to it after medicine-gram azoles is treated for Buddhist nun.The material that this patent is related to is that hydrochloric acid A Lei closes for Buddhist nun
Into a kind of key intermediate of reaction.
The intermediate it is chemical entitled:2- (4- ethyl -3- iodine) rnethyl-propanoic acid of phenyl -2, molecular formula is:C12H15IO2, English
Literary fame is 2- (4-EthyL-3-iodoPhenyL) -2-methyLpropanoic acid, and structural formula is:
The current material document report or the synthetic route applied for a patent are less, and there is course of reaction complex operation, into
This higher, low weak point of yield.
The content of the invention
The invention provides the synthetic method that a kind of hydrochloric acid A Lei replaces Buddhist nun's intermediate, simple to operate, high income, cost is more
It is low.
In order to solve the above problems, the technical solution adopted in the present invention is such, and a kind of hydrochloric acid A Lei is in the middle of Buddhist nun
The synthetic method of body, comprises the following steps:
1) using 2 bromo 2 methyl propionic acid as initiation material, add thionyl chloride progress chlorination reaction and obtain compound 1;
2) to step 1) obtained by compound 1 in add ethylo benzene, and add aluminum trichloride (anhydrous) as catalyst, substitution
Reaction obtains compound 2;
3) by step 2) obtained by compound 2 be dissolved in organic solvent, add HC (OMe)3, and add catalyst chlorination
Zinc, is heated to reflux to reaction completely, rearrangement reaction obtains compound 3;
4) by step 3) obtained by compound 3 be dissolved in organic solvent, add iodine, add acid iodide catalytic reaction, generate
Compound 4;
5) in the basic conditions, compound 4 is hydrolyzed, target product hydrochloric acid A Lei is obtained for Buddhist nun's intermediate.
In order that the more fully reaction of compound 1, it is preferable that step 1) in compound 1 and the mol ratio of thionyl chloride be 1:1
~1:1.5.
Step 2) in compound 1 and compound 2 mol ratio be 1:1~1:1.5;Mole of compound 1 and alchlor
Than for 1:1~1:1.5.
In order to reduce side reaction, step 2) detailed process be that ethylo benzene is dissolved in organic solvent, frozen cooling to -5 is taken the photograph
Below family name's degree, the compound 1 of organic solvent will be dissolved in, be slowly added dropwise into then anhydrous three alchlor, substitution reaction being added portionwise
Obtain compound 2;Wherein, described organic solvent be carbon tetrachloride, ethyl acetate, acetone, n-hexane, acetonitrile in one kind or
The mixing of two or more arbitrary proportion.
Step 3) in compound 2 and the mol ratio of trimethoxy-methane be 1:1~1:1.5, the addition of zinc chloride is change
The 5% of the mass of compound 2.Step 3) in organic solvent be carbon tetrachloride, ethyl acetate, acetone, n-hexane, acetonitrile in one kind or
It is several;
Step 4) in compound 3 and the mol ratio of iodine be 2:1, the mol ratio of iodine and acid iodide is 1:1~1:1.5;Step 4)
Middle organic solvent is the one or more in methanol, ethanol, ethyl acetate;Step 4) in reacted reaction solution through anhydrous slufuric acid
After sodium dry filter, filtrate decompression distillation, then carry out recrystallizing to obtain compound 4, recrystallization solvent used is that volume ratio is 1:2
Methanol-n-hexane or ethanol-n-hexane.
Step 5) in compound 4 and the mol ratio of alkali lye be 1:1, described alkali lye is NaOH or potassium hydroxide.
Step 5) obtained target product, crystal formation is A, the powder x-ray diffraction spectrum is 11.5,13.2,16.9,
17.5、18.1、20.0、20.6、21.1、22.0、22.5、24.9、26.3、26.5、29.1、29.5、31.6、33.2、35.1、
37.5th, there is peak at 39.3,40.2,48.5.
By step 5) obtained target product uses volume ratio for 1 again:1 acetone-n-hexane is recrystallized, and is obtained
Crystal formation is B, the X-ray diffraction spectrum of the powder is 11.5,13.2,17.5,18.1,20.0,20.4,21.1,22.0,22.5,
24.9th, at 26.3,26.5,29.1,29.5,30.1,31.6,31.8,33.2,35.1,37.5,39.3,40.2,44.8,48.5
There is peak.
By step 5) obtained target product recrystallized using ethyl acetate again, and obtained crystal formation is C, the powder X-ray-
Ray Diffraction Spectroscopy is 11.5,13.2,17.5,18.1,20.0,21.1,22.5,24.9,26.3,26.5,29.1,29.5,
31.6th, there is peak at 33.2,35.1,37.5,39.3,40.2,48.5.
Wherein, crystal formation is B and C hydrochloric acid A Lei replaces Buddhist nun's intermediate for Buddhist nun's intermediate relative to the hydrochloric acid A Lei that crystal formation is A
It is more stable.
Beneficial effect:This synthetic method, simple to operate, high income, cost is lower, and the reaction time is short, and reaction temperature is low, right
Appointed condition is less demanding, is adapted to large-scale industrial production, and industrial prospect is good.
Brief description of the drawings
Fig. 1 is crystal formation A powder x-ray diffraction figure;
Fig. 2 is crystal formation B powder x-ray diffraction figure;
Fig. 3 is crystal formation C powder x-ray diffraction figure;
Embodiment
In order to deepen the understanding of the present invention, below in conjunction with embodiment, the invention will be further described, the embodiment
It is only used for explaining the present invention, is not intended to limit the scope of the present invention..
The reaction scheme of embodiment 1-3 synthetic methods is as follows:
Embodiment 1
1) 15g 2 bromo 2 methyl propionic acids are added in 20g thionyl chlorides, after stirring at normal temperature is reacted 4 hours, is warming up to 80
Degree Celsius backflow 2 hours, vacuum distillation obtains compound 1, and weight is 16.5g, and yield is 99%.
2) 11.5g ethylo benzenes are weighed and add reaction bulb, solvent 100mL carbon tetrachloride are added, chilled water is cooled to -5 and taken the photograph
Below family name's degree, compound 1 is dissolved in 50mL carbon tetrachloride, is slowly added dropwise after reaction bulb, then anhydrous three trichlorines of 14g are added portionwise
Change aluminium, keeping temperature and stirring reaction 10 hours, then add 100mL20% hydrochloric acid solutions, stir 0.5 hour, stratification,
Organic layer is first washed till neutrality with 10% sodium carbonate liquor, is washed with water and washs twice, vacuum distillation obtains compound 2, weight
For 22.5g, yield is 99%.
3) 200mL acetone as solvent is used, compound 2 is added, trimethoxy-methane 11.5g, zinc chloride 1g are heated to reflux anti-
Answer 6 hours, filtered after the near room temperature of equitemperature, it is 7 that filtrate, which is washed with 5% sodium acid carbonate to PH, is washed with water and washs twice, organic
Layer anhydrous sodium sulfate drying, filtering, filtrate step-down distillation obtains compound 3, weight is 15g, and yield is 83% to drying.
4) compound 3 is dissolved in 200mL ethanol, is slowly added to iodine 9.5g, stirred, 0.1g acid iodide is slowly added dropwise as catalysis
Agent, is reacted 8 hours, then it is 7 to be washed with 5% sodium sulfite solution to PH, and washing twice, is filtered with anhydrous sodium sulfate drying, is filtered
Liquid vacuum distillation, again with methanol-n-hexane is recrystallized, and obtained solid is compound 4, and weight is 20g, and yield is
83%.
5) 2.5g NaOH is dissolved in 100mL water, water-bath keeping temperature is no more than 20 degrees Celsius, stirring is lower slowly to be added
Enter compound 4, react 3 hours, then 2.3g hydrochloric acid is dissolved in the weak solution obtained in 20mL water to add in reaction bulb, reaction 0.5
Hour, concussion after 3g activated carbons is added in solution and is filtered after 3 minutes, filtrate is extracted with ethyl acetate, obtained organic layer nothing
Aqueous sodium persulfate is filtered after drying, and the solid that filtrate decompression distillation is obtained is target product, and weight is 19.2g, and yield is 100%.
Gross production rate is:67%.
To step 5) product progress XRD diffraction analysis crystal formation (used INSTRUMENT MODEL is Neo-Confucianism D/MAX-3C) is obtained,
Result is obtained for shown in Fig. 1, the X-ray diffraction spectrum of the powder is 11.5,13.2,16.9,17.5,18.1,20.0,20.6,
21.1st, at 22.0,22.5,24.9,26.3,26.5,29.1,29.5,31.6,33.2,35.1,37.5,39.3,40.2,48.5
There is peak.
Embodiment 2
1) 15g 2 bromo 2 methyl propionic acids are added in 10g thionyl chlorides, after stirring at normal temperature is reacted 4 hours, is warming up to 80
Degree Celsius backflow 2 hours, vacuum distillation obtains compound 1, and weight is 15.8g, and yield is 95%.
2) 9g2 ethylo benzenes are weighed and add reaction bulb, solvent 100mL ethyl acetate are added, it is Celsius that chilled water is cooled to -5
Degree below, by step 1) obtained by compound 1 be dissolved in 50mL ethyl acetate, be slowly added dropwise after reaction bulb, then 11g is added portionwise
Anhydrous three alchlor, keeping temperature and stirring reaction 10 hours, then add 100mL20% hydrochloric acid solutions, and stirring 0.5 is small
When, organic layer is first washed till neutrality with 10% sodium carbonate liquor, is washed with water and washs twice, vacuum distillation is obtained by stratification
Compound 2, weight is 20g, and yield is 92%.
3) use 200mL acetone as solvent, add step 2) obtained by compound 2, trimethoxy-methane 8.3g, zinc chloride
Filtered after 1g, heating reflux reaction 6 hours, the near room temperature of equitemperature, it is 7 that filtrate, which is washed with 5% sodium acid carbonate to PH, then uses water
Wash twice, organic layer anhydrous sodium sulfate drying, filter, filtrate step-down distillation obtains compound 3, weight is to drying
12.3g, yield is 76%.
4) by step 3) obtained by chemical combination 3 be dissolved in 200mL ethyl acetate, be slowly added to iodine 7.6g, stir, be slowly added dropwise
5.3g acid iodide reacts 8 hours as oxidant, then it is 7 to be washed with 5% sodium sulfite solution to PH, and washing twice, uses anhydrous sulphur
Sour sodium dry filter, filtrate decompression distillation, again with methanol is recrystallized with n-hexane, and obtained solid is compound 4, weight
For 16g, yield is 81%.
5) 2g NaOH is dissolved in 100mL water, water-bath keeping temperature is no more than 20 degrees Celsius, is slowly added under stirring
Step 3) obtained by compound 4, react 3 hours, then 2g hydrochloric acid be dissolved in the weak solution that is obtained in 20mL water and add in reaction bulb,
Reaction 0.5 hour, adds concussion after 3g activated carbons and is filtered after 3 minutes, filtrate is extracted with ethyl acetate, and what is obtained is organic in solution
Filtered after layer anhydrous sodium sulfate drying, the solid that filtrate decompression distillation is obtained is target product, and weight is 15.2g, and yield is
100%.
Gross production rate is:53%.
Embodiment 3
1) 15g 2 bromo 2 methyl propionic acids are added in 20g thionyl chlorides, after stirring at normal temperature is reacted 4 hours, is warming up to 80
Degree Celsius backflow 2 hours, vacuum distillation obtains compound 1, and weight is 16.7g, and yield is 100%.
2) weigh the ethylo benzene of 14.3g raw materials 2 and add reaction bulb, add solvent 100mL acetonitriles, chilled water is cooled to -5 and taken the photograph
Below family name's degree, by step 1) obtained by compound 1 be dissolved in 50mL acetonitriles, be slowly added dropwise after reaction bulb, then be added portionwise 18g without
The alchlor of water three, keeping temperature and stirring reaction 10 hours, then add 100mL20% hydrochloric acid solutions, stir 0.5 hour,
Stratification, is first washed till neutrality with 10% sodium carbonate liquor by organic layer, is washed with water and washs twice, vacuum distillation obtains chemical combination
Thing 2, weight is 22.1g, and yield is 96%.
3) make solvent with 200mL n-hexanes, add step 2) gained compound 2, trimethoxy-methane 14g, zinc chloride 1g,
Filtered after heating reflux reaction 6 hours, the near room temperature of equitemperature, it is 7 that filtrate, which is washed with 5% sodium acid carbonate to PH, is washed with water
Wash twice, organic layer anhydrous sodium sulfate drying, filter, filtrate step-down distillation obtains compound 3, weight is to drying
14.1g, yield is 79%.
4) by step 3) obtained by compound 3 be dissolved in 200mL ethyl acetate, be slowly added to iodine 9.3g, stir, be slowly added dropwise
6.4g acid iodide reacts 8 hours as oxidant, then it is 7 to be washed with 5% sodium sulfite solution to PH, and washing twice, uses anhydrous sulphur
Sour sodium dry filter, filtrate decompression distillation, then recrystallized with ethanol with n-hexane, obtained solid is compound 4, weight
For 19.1g, yield is 84%.
5) 2.3g NaOH is dissolved in 100mL water, water-bath keeping temperature is no more than 20 degrees Celsius, stirring is lower slowly to be added
Enter step 4) obtained by compound 4, react 3 hours, then 2.1g hydrochloric acid be dissolved in the weak solution that is obtained in 20mL water and add reaction
In bottle, react 0.5 hour, concussion after 3g activated carbons is added in solution and is filtered after 3 minutes, filtrate is extracted with ethyl acetate, obtained
Organic layer anhydrous sodium sulfate drying after filter, the obtained solid of filtrate decompression distillation is product, and weight is 18.8g, yield
For 99%.
Gross production rate is:66%.
Embodiment 4
By step 5) obtained target product volume ratio is 1:1 acetone-n-hexane is dissolved, after stirring 30 minutes
Refrigeration is stood in 0-8 degrees Celsius, separates out and filtered after crystal, dry, obtained crystal formation is B, and XRD diffraction analysis is carried out to crystal B
Crystal formation (used INSTRUMENT MODEL is Neo-Confucianism D/MAX-3C), it is the X-ray diffraction spectrum of the powder shown in Fig. 2 to obtain result
11.5,13.2,17.5,18.1,20.0,20.4,21.1,22.0,22.5,24.9,26.3,26.5,29.1,29.5,30.1,
31.6th, there is peak at 31.8,33.2,35.1,37.5,39.3,40.2,44.8,48.5.
Embodiment 5
By step 5) obtained target product dissolved with ethyl acetate, and stirring 30 minutes is after 0-8 degrees Celsius of standing
Refrigeration, separates out and filtered after crystal, dry, and XRD diffraction analysis crystal formation is carried out to crystal C, and (used INSTRUMENT MODEL is Neo-Confucianism D/
MAX-3C), obtain result for shown in Fig. 3, the X-ray diffraction spectrum of the powder is 11.5,13.2,17.5,18.1,20.0,
21.1st, there is peak at 22.5,24.9,26.3,26.5,29.1,29.5,31.6,33.2,35.1,37.5,39.3,40.2,48.5.
Presently preferred embodiments of the present invention is the foregoing is only, is not intended to limit the invention, all essences in the present invention
Within refreshing and principle, any modifications, equivalent substitutions and improvements made etc..
Claims (10)
1. a kind of hydrochloric acid A Lei replaces the synthetic method of Buddhist nun's intermediate, it is characterised in that comprise the following steps:
1) using 2 bromo 2 methyl propionic acid as initiation material, add thionyl chloride progress chlorination reaction and obtain compound 1;
2) to step 1) obtained by compound 1 in add ethylo benzene, and add aluminum trichloride (anhydrous) as catalyst, substitution reaction
Obtain compound 2;
3) by step 2) obtained by compound 2 be dissolved in organic solvent, add HC (OMe)3, and catalyst zinc chloride is added, heat
It is back to reaction complete, rearrangement reaction obtains compound 3;
4) by step 3) obtained by compound 3 be dissolved in organic solvent, add iodine, add acid iodide catalytic reaction, generate chemical combination
Thing 4;
5) in the basic conditions, compound 4 is hydrolyzed, target product hydrochloric acid A Lei is obtained for Buddhist nun's intermediate.
2. a kind of hydrochloric acid A Lei according to claim 1 replaces the synthetic method of Buddhist nun's intermediate, it is characterised in that step 1) in
Compound 1 and the mol ratio of thionyl chloride are 1:1~1:1.5.
3. a kind of hydrochloric acid A Lei according to claim 1 replaces the synthetic method of Buddhist nun's intermediate, it is characterised in that step 2) in
The mol ratio of compound 1 and compound 2 is 1:1~1:1.5;Compound 1 and the mol ratio of alchlor are 1:1~1:1.5.
4. a kind of hydrochloric acid A Lei according to claim 1 replaces the synthetic method of Buddhist nun's intermediate, it is characterised in that step 2)
Detailed process is that ethylo benzene is dissolved in into organic solvent, and frozen cooling will be dissolved in the compound of organic solvent to less than -5 degrees Celsius
1, it is slowly added dropwise into then anhydrous three alchlor being added portionwise, substitution reaction obtains compound 2;Wherein, described organic solvent
For one kind in carbon tetrachloride, ethyl acetate, acetone, n-hexane, acetonitrile or the mixing of two or more arbitrary proportion.
5. a kind of hydrochloric acid A Lei according to claim 1 replaces the synthetic method of Buddhist nun's intermediate, it is characterised in that step 3) in
Compound 2 and the mol ratio of trimethoxy-methane are 1:1~1:1.5, the addition of zinc chloride is the 5% of the mass of compound 2.
6. a kind of hydrochloric acid A Lei according to claim 1 replaces the synthetic method of Buddhist nun's intermediate, it is characterised in that step 4) in
Compound 3 and the mol ratio of iodine are 2:1, the mol ratio of iodine and acid iodide is 1:1~1:1.5.
7. a kind of hydrochloric acid A Lei according to claim 1 replaces the synthetic method of Buddhist nun's intermediate, it is characterised in that step 5) in
Compound 4 and the mol ratio of alkali lye are 1:1, described alkali lye is NaOH or potassium hydroxide.
8. a kind of hydrochloric acid A Lei according to claim 1 replaces the synthetic method of Buddhist nun's intermediate, it is characterised in that step 5)
The target product arrived, crystal formation is A, the powder x-ray diffraction spectrum is 11.5,13.2,16.9,17.5,18.1,20.0,
20.6、21.1、22.0、22.5、24.9、26.3、26.5、29.1、29.5、31.6、33.2、35.1、37.5、39.3、40.2、
There is peak at 48.5.
9. a kind of hydrochloric acid A Lei according to claim 1 replaces the synthetic method of Buddhist nun's intermediate, it is characterised in that by step 5)
Obtained target product uses volume ratio for 1 again:1 acetone-n-hexane is recrystallized, obtained crystal formation be B, the powder X-ray-
Ray Diffraction Spectroscopy is 11.5,13.2,17.5,18.1,20.0,20.4,21.1,22.0,22.5,24.9,26.3,26.5,
29.1st, there is peak at 29.5,30.1,31.6,31.8,33.2,35.1,37.5,39.3,40.2,44.8,48.5.
10. a kind of hydrochloric acid A Lei according to claim 1 replaces the synthetic method of Buddhist nun's intermediate, it is characterised in that by step
5) target product obtained is recrystallized using ethyl acetate again, and obtained crystal formation is C, and the powder x-ray diffraction spectrum exists
11.5、13.2、17.5、18.1、20.0、21.1、22.5、24.9、26.3、26.5、29.1、29.5、31.6、33.2、35.1、
37.5th, there is peak at 39.3,40.2,48.5.
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CN110105204A (en) * | 2019-06-04 | 2019-08-09 | 荆楚理工学院 | A kind of 4- (the halogenated isobutyryl of 2-) benzyl carbinol derivative and preparation method thereof |
CN112047829A (en) * | 2020-08-31 | 2020-12-08 | 成都艾必克医药科技有限公司 | Synthetic method of hydrochloric acid Alininib intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid |
CN112047829B (en) * | 2020-08-31 | 2023-05-26 | 成都艾必克医药科技有限公司 | Synthesis method of alcaine intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid |
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