CN115504923A - Preparation method of 7-ethyl tryptophol - Google Patents

Preparation method of 7-ethyl tryptophol Download PDF

Info

Publication number
CN115504923A
CN115504923A CN202110690746.XA CN202110690746A CN115504923A CN 115504923 A CN115504923 A CN 115504923A CN 202110690746 A CN202110690746 A CN 202110690746A CN 115504923 A CN115504923 A CN 115504923A
Authority
CN
China
Prior art keywords
reaction
compound
solution
preparation
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202110690746.XA
Other languages
Chinese (zh)
Inventor
马永杰
鲍广龙
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shandong New Time Pharmaceutical Co Ltd
Original Assignee
Shandong New Time Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong New Time Pharmaceutical Co Ltd filed Critical Shandong New Time Pharmaceutical Co Ltd
Priority to CN202110690746.XA priority Critical patent/CN115504923A/en
Publication of CN115504923A publication Critical patent/CN115504923A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms

Landscapes

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

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of 7-ethyl tryptophol. The invention takes 7-ethyl indole-3-formaldehyde as an initial material, and the 7-ethyl tryptophol can be prepared by hydroboration oxidation after the reaction with methyl triphenyl phosphonium halide. The preparation method can effectively avoid the problems of more product impurities, difficult purification and lower yield caused by adopting a Fischer Indole synthesis method in the prior art; meanwhile, the use of a highly toxic KCN is effectively avoided, the operation safety is improved, and the target product is purified without a reduced pressure fractionation operation, so that the production operation is simplified; the preparation process of the 7-ethyl tryptophol is simple and convenient to operate, and the obtained product has high yield and purity and is suitable for industrial production.

Description

Preparation method of 7-ethyl tryptophol
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of 7-ethyl tryptophol.
Background
Etodolac (Etodolac) is a potent nonsteroidal anti-inflammatory analgesic, is used for treating rheumatoid arthritis, osteoarthritis and other symptoms, has the characteristics of good tolerance, light toxic and side effects, strong analgesic effect and the like, has few gastrointestinal adverse reactions, and is particularly suitable for elderly patients. The drug is developed by AHP Wyeth-Ayesrt company in the United states, is firstly marketed in the United kingdom in 1985, and has the following chemical structural formula:
Figure BDA0003126609160000011
the 7-ethyl tryptophol is used as a key intermediate for synthesizing etodolac, directly influences the production, market supply and quality problems of the drug, and has the following chemical structural formula:
Figure BDA0003126609160000012
the preparation methods reported at present for 7-ethyl tryptophol mainly comprise the following methods:
US4062869A, US2006166947A1 and document 7-ethyl-1H-indole synthesis, jiangsu chemical engineering, 1993,21 (1), 17-19, 7-ethyl indole synthesis, chinese medicinal chemistry journal, 1997,7 (1), 57-59, heterocyclic, 2018,96 (1), 67-73 report that o-nitroethylbenzene or its downstream intermediate, which is the by-product of industrial chloromycetin intermediate p-nitroethylbenzene, is used as raw material, o-ethylaniline is obtained by tin powder/hydrochloric acid reduction, then oximidoacetamide derivative is formed with hydrated chloral and hydroxylamine hydrochloride under acidic condition, 7-ethyl indolinone is obtained by cyclization in concentrated sulfuric acid, 7-ethyl indoline is obtained by reduction with lithium aluminium hydride, finally 7-ethyl indole is reacted with oxalyl chloride, and then esterification and sodium borohydride reduction are carried out:
Figure BDA0003126609160000013
however, the above process has the disadvantages of long synthetic route, inconvenient operation, low overall yield, high risk of the reducing agent, high price and unsuitability for industrial production.
US4585877A and the research on Etodolac synthetic process, tianjin chemical engineering, 2004,18 (5), 22-23, etodolac synthetic process, chemical reports, 2005,56 (8), 1536-1540, also using o-nitroethylbenzene as raw material, obtaining o-ethylaniline by iron powder reduction, then after diazotization reaction, reducing with sodium sulfite (sodium bisulfite or stannous chloride) to obtain o-ethylphenylhydrazine hydrochloride, then reflux reacting with 2,3-dihydrofuran in 1,4-dioxane to obtain:
Figure BDA0003126609160000021
the Fischer Indole synthesis method is a mainstream process for producing 7-ethyl tryptophol at present, and is the simplest synthesis method with the lowest production cost in the prior art. The Fischer Indole synthesis only seems to be a cleaner synthesis from the reaction formula, but the method is not actually used for synthesizing 7-ethyl tryptophol, and on one hand, the technology needs a large amount of environmentally-friendly organic solvents such as acetonitrile, DMF, DMAc, isobutanol and the like or expensive solvents, and the solvent recovery rate is low; on the other hand, strong acid is required for catalyzing the Fischer rearrangement reaction to form the indole ring, but the strong acid can also catalyze the indole ring to generate chain reaction to generate purple-black sticky polymers, so that a plurality of impurities are generated, the purity of a crude product is low, the post-treatment is complex, and the product 7-ethyl tryptophol obtained through reaction separation is a dark-colored (usually brown-black) sticky jelly or oily substance. The separation and purification of such a low-purity dark gum has been reported to be a silica gel column separation method (see U.S. Pat. Nos. 4585877 and WO 9959970) and an extraction separation method (see WO 2005002523), and the like. Although the silica gel column separation method can obtain the product 7-ethyl tryptophol with high purity, the use of a large amount of solvent is not economical and is not practical in industrial production. Although the extraction separation method is an effective method for improving the purity of the industrial 7-ethyl tryptophol at present, the purity of the crude 7-ethyl tryptophol (the content is usually 60-85%) is still only 95-97% after separation and purification, and the color of the product is dark brown (see WO 2005002523), which is still unsatisfactory.
In addition, after indole cyclization, the system contains unreacted aldehyde (obtained by hydrolyzing 2,3-dihydrofuran) and 2,3-dihydrofuran, so that the following three byproducts are easily generated, the purity of a crude product is low, and the post-treatment is complex:
Figure BDA0003126609160000022
in addition, the process uses 2,3-dihydrofuran with higher price, so that the production cost is correspondingly increased.
Chinese patent application CN1740153A, CN1740154A and document 7-New Synthesis Process of Ethyl tryptol, proc. University of chemical engineering, 2010,24 (1), 127-131, is to hydrolyze 2,3-dihydrofuran under acidic condition to obtain 4-hydroxybutyraldehyde, then use "one pot method" to react with o-ethyl phenylhydrazine salt to generate 4-hydroxybutyraldehyde o-ethyl phenylhydrazone, finally Fischer ring formation under concentrated sulfuric acid or glycol ether solvent condition, then vacuum distillation or cyclohexane recrystallization to obtain the target product:
Figure BDA0003126609160000031
however, the above process still has the disadvantages of Fischer Indole synthesis and the use of 2,3-dihydrofuran, which is expensive.
Similarly, chinese patent application CN107522649A and the literature Chemical Engineering & Processing, process Induction, 121 (2017) 144-148 adopt a tubular continuous flow reaction technology adopting microwave heating to react phenylhydrazine hydrochloride with 4-hydroxybutyraldehyde, thereby realizing the continuous synthesis reaction of 7-ethyl tryptophol. Although the use of strong acid in the Fischer Indole synthesis method is avoided theoretically, the process has limited batch quantity and is not suitable for industrial scale-up production.
The document Heterocycles,2003,60 (5) 1095-1110 adopts the active precursor 3-ethoxytetrahydrofuran of 2,3-dihydrofuran as the donor of 4-hydroxybutyraldehyde, which also cannot avoid the problem of high production cost:
Figure BDA0003126609160000032
the Journal of laboratory Compounds and Radiopharmaceuticals, vol.XIV, no.3,1978,411-425, modified the strategy to prepare the compound by hydrolytic reduction after introduction of the cyano group in the 3-substituted-7-ethylindole:
Figure BDA0003126609160000033
however, the process applies the highly toxic KCN, so that the operation risk is high, the obtained cyano-substituted intermediate has 2-bit isomer impurities, the purity of the obtained product is low, and in addition, the carboxylic acid reduction uses lithium aluminum hydride with high price and high risk, so that the operation safety is low, and the industrial scale-up production is difficult.
In addition, the Journal of Medicinal Chemistry,1976,19 (3), 391-395, has been designed and synthesized for the related indolinone derivatives by using Reformatsky reaction, but this process also requires the use of relatively expensive and dangerous lithium aluminum hydride:
Figure BDA0003126609160000034
in addition, the documents Organic Syntheses, col. Vol.9, p.417 (1998); vol.74, p.248 (1997) firstly uses tert-butyldimethylsilyl chloride (TMDMSCl) to protect 1-position indole hydrogen under the condition of n-butyllithium, introduces bromine at 3-position through NBS, and then performs nucleophilic substitution with propylene oxide after Li substitution under the condition of n-butyllithium, and performs deprotection to obtain related derivatives:
Figure BDA0003126609160000041
however, the process has the advantages of more synthesis steps, more complicated operation and lower overall yield; meanwhile, the method needs to be applied to a dangerous reagent n-butyllithium for many times, so that the operation safety is low, and the industrial scale-up production is difficult.
In summary, the existing preparation method of 7-ethyl tryptophol has various defects of high process risk, complex operation, low yield, high production cost and the like, so that the research and search of a reaction route which has mild reaction conditions, simple and convenient operation process, high product yield, high purity and low production cost and is suitable for industrial production of 7-ethyl tryptophol still needs to solve the problem at present.
Disclosure of Invention
Aiming at the problems of the existing 7-ethyl tryptophol preparation technology, the invention provides a novel preparation method of 7-ethyl tryptophol. The method has mild reaction conditions and simple and convenient operation process, and the prepared target product has higher purity and yield.
The specific technical scheme of the invention is as follows:
a preparation method of 7-ethyl tryptophol comprises the following steps:
step 1, under the protection of inert gas, SM-2 firstly reacts under alkaline conditions, then SM-1 is added for continuous reaction, and a compound I-1 is prepared;
step 2, adding the compound I-1 into THF solution of a boron reagent for reaction, and reacting with hydrogen peroxide under an alkaline condition to obtain a compound I;
the reaction route is as follows:
Figure BDA0003126609160000042
wherein X in SM-2 is one of Br and I.
Preferably, the preparation method of the 7-ethyl tryptophol specifically comprises the following steps:
step 1, controlling the temperature T under the protection of inert gas 1 Adding alkali/organic solvent A solution into organic solvent A of SM-2 for reaction, adding SM-1 into the reaction solution, heating to room temperature, and continuing the reaction to obtain a compound I-1;
step 2, adding the compound I-1 into THF solution of boron reagent, reacting at room temperature until the raw material I-1 completely reacts, adding a proper amount of water and inorganic alkali solution, and controlling the temperature T 2 Adding hydrogen peroxide, and reacting at room temperature to obtain the compound I.
Preferably, the inert gas in step 1 is one of nitrogen and argon.
Preferably, the SM-2 in the step 1 is one selected from methyl triphenyl phosphonium bromide and methyl triphenyl phosphonium iodide, and is preferably methyl triphenyl phosphonium bromide.
Preferably, the base in step 1 is selected from one of t-BuOK, KHMDS, naHMDS, preferably KHMDS.
Preferably, the organic solvent A in step 1 is one selected from tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and diethyl ether, and is preferably tetrahydrofuran.
Preferably, the feeding molar ratio of the compounds SM-1 and SM-2 and the base in the step 1 is 1: 1.2-2.5: 1.2 to 3.0, preferably 1:1.5:1.65.
preferably, the reaction temperature T in step 1 is between-10 and 10 ℃, preferably between-5 and 0 ℃.
In a preferred scheme, after the reaction in step 1 is finished, post-treatment operation is required, and the specific steps are as follows: filtering, pouring the filtrate into purified water, extracting with organic solvent B, mixing organic layers, concentrating, and drying to obtain compound I-1; the organic solvent B is one or the combination of dichloromethane, chloroform, ethyl acetate and methyl tert-butyl ether, preferably dichloromethane.
Preferably, the boron reagent in step 2 is selected from BH 3 ·Me 2 S、9-BBN、Sia 2 BH. borane-N, N-dimethylaniline, preferably 9-BBN.
Preferably, the feeding molar ratio of the compound I-1 to the boron reagent and hydrogen peroxide in the step 2 is 1:1.1 to 1.5:3.0 to 6.0, preferably 1:1.2:4.0.
preferably, the inorganic base in step 2 is selected from one of NaOH and KOH, preferably NaOH.
Preferably, the concentration of the inorganic base solution in the step 2 is usually 3mol/L.
Preferably, the feeding molar ratio of the inorganic alkali to the hydrogen peroxide in the step 2 is 1-1.1: 1, preferably 1.05:1.
preferably, the appropriate amount of water in step 2 is an amount capable of quenching the remaining boron reagent.
Preferably, the temperature control T in the step 2 2 Is-10 to 5 ℃, preferably-5 to-2 ℃.
In a preferred scheme, after the reaction in step 2 is finished, post-treatment operation is required, and the specific steps are as follows: adjusting the pH of the solution to be 10 by alkali, extracting by an organic solvent, combining organic phases, washing by a saturated sodium thiosulfate solution or a saturated sodium sulfite solution, washing by a saturated saline solution, concentrating the organic phase under reduced pressure, and drying to obtain a target product I. The base is common inorganic base such as NaOH, KOH, na 2 CO 3 、K 2 CO 3 Etc.; the organic solvent is selected from one or a combination of dichloromethane, chloroform, ethyl acetate and methyl tert-butyl ether, and dichloromethane is preferred.
The invention has the beneficial effects that:
the invention provides a novel preparation method of 7-ethyl tryptophol, which takes 7-ethyl indole-3-formaldehyde as a starting material to react with SM-2 and then undergo hydroboration and oxidation to prepare the 7-ethyl tryptophol. The method can effectively avoid the problems of more product impurities, difficult purification and lower yield caused by adopting a Fischer Indole synthesis method; meanwhile, the use of a highly toxic KCN is effectively avoided, the operation safety is improved, and the target product is purified without a reduced pressure fractionation operation, so that the production operation is simplified; the preparation process of the 7-ethyl tryptophol is simple and convenient to operate, and the obtained product has high yield and purity and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to illustrate the present invention, not to limit the present invention, therefore, the simple modifications of the present invention in the method of the present invention are within the scope of the present invention as claimed. The boron reagents described herein are commercially available or can be prepared according to the prior art.
The structure of the 7-ethyl tryptophol compound obtained by the invention is confirmed as follows:
Figure BDA0003126609160000061
ESI-HRMS(m/z)：190.1232[M+H] + ； 1 H-NMR(600MHz,DMSO-d 6 )δ8.04(s,1H),7.45(dd,J＝7.78、1.02Hz,1H),7.08(t,J＝7.21Hz,1H),7.02～7.04(m,2H),3.90(t,J＝6.35Hz,2H),3.03(dt,J＝6.11、0.68Hz,2H),2.85(q,J＝7.58Hz,2H),1.70(s,1H),1.35(t,J＝7.60Hz,3H)； 13 C-NMR(151MHz,CDCl 3 )δ135.28,127.10,126.64,122.23,120.54,119.75,116.56,112.54,62.64,28.91,23.95,13.80.
in the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Synthesis of Compound I
Example 1
Under the protection of argon, controlling the temperature to be-5-0 ℃, adding a KHMDS/THF (16.5 ml,16.5 mmol) solution into THF (30 ml) of methyl triphenyl phosphonium bromide (5.36g, 15mmol), stirring for reacting for 1h, adding SM-1 (1.73g, 10mmol) into the reaction solution, continuing heating to room temperature for reacting, after the detection reaction is finished, filtering, pouring the filtrate into purified water (50 ml), extracting dichloromethane (30 ml multiplied by 3), combining organic phases, concentrating and drying to obtain a compound I-1, wherein the obtained compound I-1 can be directly used in the next reaction.
Adding the compound I-1 (calculated by 10 mmol) obtained above into a THF (30 mL) solution of 9-BBN (1.46g, 12mmol), reacting at room temperature until the reaction of the raw material I-1 is completed, adding a proper amount of water and a 3M NaOH solution (14mL, 42mmol), adding hydrogen peroxide (omega =30%,15mL, 40mmol) at the temperature of-5 to-2 ℃, continuing to react at room temperature until the reaction is completed, adjusting the pH of the solution to be =10 by using NaOH, then extracting by dichloromethane (30 mL × 3), combining organic phases, washing by a saturated sodium thiosulfate solution (30 mL × 3), washing by a saturated saline solution (30 mL), concentrating by organic phase under reduced pressure, and drying to obtain the target product I, wherein the yield is 93.7% and the purity is 98.90%.
Example 2
Controlling the temperature to be 0-5 ℃ under the protection of argon, adding t-BuOK/DMF (16.5mL, 16.5 mmol) into DMF (30 mL) of methyl triphenyl phosphonium bromide (4.29g, 12mmol), stirring for reacting for 1h, adding SM-1 (1.73g, 10mmol) into the reaction liquid, continuing to rise to room temperature for reacting, detecting after the reaction is finished, filtering, adding the filtrate into purified water (50 mL), extracting dichloromethane (30 mL multiplied by 3), combining organic phases, concentrating and drying to obtain a compound I-1, wherein the obtained compound I-1 can be directly used in the next reaction.
Adding the compound I-1 (calculated by 10 mmol) obtained above into a THF (30 mL) solution of 9-BBN (1.34g, 11mmol), reacting at room temperature until the reaction of the raw material I-1 is completed, adding a proper amount of water and a 3M KOH solution (14mL, 42mmol), adding hydrogen peroxide (omega =30%,15mL, 40mmol) at the temperature of-5 to-2 ℃, continuing to react at room temperature until the reaction is completed, adjusting the pH of the solution to be =10 by KOH, extracting by dichloromethane (30 mL x 3), combining organic phases, washing by a saturated sodium thiosulfate solution (30 mL x 3), washing by a saturated saline solution (30 mL), concentrating by an organic phase under reduced pressure, and drying to obtain the target product I, wherein the yield is 91.0% and the purity is 98.81%.
Example 3
Controlling the temperature to be 5-10 ℃ under the protection of nitrogen, adding a KHMDS/THF (16.5ml, 16.5mmol) solution into methyl triphenyl phosphonium bromide (3.93g, 11mmol) THF (30 ml), stirring for reacting for 0.5h, adding SM-1 (1.73g, 10mmol) into the reaction solution, continuing heating to room temperature for reacting, detecting after the reaction is finished, filtering, adding the filtrate into purified water (500 ml), extracting with chloroform (30 ml multiplied by 3), combining organic phases, concentrating, drying to obtain a compound I-1, wherein the obtained compound I-1 can be directly used in the next reaction.
Adding the compound I-1 (calculated by 10 mmol) obtained in the previous step into THF (30 mL) solution of 9-BBN (1.28g, 10.5 mmol), reacting at room temperature until the reaction of the raw material I-1 is completed, adding a proper amount of water and 3M NaOH solution (14mL, 42mmol), controlling the temperature to be-10 to-5 ℃, adding hydrogen peroxide (omega =30%,15mL, 40mmol), continuing to react at room temperature until the reaction is finished, and adding Na 2 CO 3 The solution pH =10 was adjusted, followed by chloroform (30 mL × 3) extraction, and the organic phases were combined, washed with a saturated sodium thiosulfate solution (30 mL × 3), washed with a saturated saline solution (30 mL), concentrated under reduced pressure with the organic phase, and dried to obtain the objective product I with a yield of 86.1% and a purity of 98.25%.
Example 4
Controlling the temperature to be-10 to-5 ℃ under the protection of argon, adding a NaHMDS/DMSO (16.5 ml,16.5 mmol) solution into DMSO (30 ml) of methyltriphenylphosphonium bromide (8.93g, 25mmol), stirring for reacting for 1h, adding SM-1 (1.73g, 10mmol) into the reaction solution, continuing to rise to room temperature for reaction, detecting the reaction is finished, filtering, adding the filtrate into purified water (50 ml), extracting dichloromethane (30 ml multiplied by 3), combining organic phases, concentrating and drying to obtain a compound I-1, wherein the obtained compound I-1 can be directly used in the next reaction.
Adding the compound I-1 (calculated by 10 mmol) obtained in the previous step into THF (30 mL) solution of 9-BBN (1.83g, 15mmol) for reacting at room temperature till the raw material I-1 is completely reacted, adding a proper amount of water and 3M NaOH solution (14mL, 42mmol), adding hydrogen peroxide (omega =30%,15mL, 40mmol) at the temperature of-2-5 ℃, continuing to react at room temperature till the reaction is finished, and adding K 2 CO 3 Adjust solution pH =10, then ethyl acetate (30 ml in a prepared extract)3) Extracting, combining organic phases, washing by saturated sodium thiosulfate solution (30 mL multiplied by 3), washing by saturated saline solution (30 mL), concentrating by organic phase under reduced pressure, and drying to obtain the target product I, wherein the yield is 92.6%, and the purity is 98.75%.
Example 5
Controlling the temperature to-10-5 ℃ under the protection of argon, and adding methyl triphenyl phosphonium bromide (9.29g, 26mmol) into Et 2 O (30 ml) was added with t-BuOK/Et 2 O (16.5ml, 16.5mmol) solution is stirred to react for 1.5h, then SM-1 (1.73g, 10mmol) is added into the reaction solution, the reaction solution is continuously heated to room temperature for reaction, after the reaction is detected to be finished, the reaction solution is filtered, the filtrate is added into purified water (50 ml), ethyl acetate (30 ml multiplied by 3) is used for extraction, organic phases are combined, the concentration and the drying are carried out, and a compound I-1 is prepared, and the obtained compound I-1 can be directly used in the next reaction.
Adding the compound I-1 (calculated by 10 mmol) obtained above into THF (30 mL) solution of 9-BBN (1.95g, 116mmol), reacting at room temperature until the reaction of the raw material I-1 is completed, adding a proper amount of water and 3M NaOH solution (14mL, 42mmol), adding hydrogen peroxide (omega =30%,15mL, 40mmol) at the temperature of-5 to-2 ℃, continuing to react at room temperature until the reaction is completed, adjusting the pH of the solution to be =10 by using NaOH, extracting by using dichloromethane (30 mL x 3), combining organic phases, washing by using saturated sodium thiosulfate solution (30 mL x 3), washing by using saturated saline (30 mL), concentrating by using organic phase under reduced pressure, and drying to obtain the target product I, wherein the yield is 88.2% and the purity is 98.11%.
Example 6
Controlling the temperature to be 5-10 ℃ under the protection of argon, adding KHMDS/THF (12.0ml, 12mmol) solution into THF (30 ml) of methyl triphenyl phosphine iodide (6.06g, 15mmol), stirring and reacting for 0.5h, adding SM-1 (1.73g, 10mmol) into the reaction solution, continuing to rise to room temperature for reaction, detecting after the reaction is finished, filtering, adding the filtrate into purified water (50 ml), extracting dichloromethane (30 ml multiplied by 3), combining organic phases, concentrating and drying to obtain a compound I-1, wherein the obtained compound I-1 can be directly used in the next reaction.
Compound I-1 obtained above (in 10 mmol) was added to BH 3 ·Me 2 S (0.91g, 12mmol) in THF (30 mL) at room temperature until the reaction of the raw material I-1 is completed, adding appropriate amount of water and 3M NaOH solutionAdding hydrogen peroxide (omega =30%,11.25mL and 30mmol) into the solution (10.5mL and 31.5mmol) at the temperature of-5 to-2 ℃, continuing to react at room temperature until the reaction is finished, adjusting the pH of the solution to be =10 by NaOH, then extracting by dichloromethane (30 mL multiplied by 3), combining organic phases, washing by a saturated sodium thiosulfate solution (30 mL multiplied by 3), washing by a saturated saline solution (30 mL), concentrating by the organic phase under reduced pressure, and drying to obtain the target product I, wherein the yield is 91.5%, and the purity is 98.55%.
Example 7
Controlling the temperature to be-10 to-5 ℃ under the protection of argon, adding KHMDS/THF (30ml, 30mmol) solution into THF (30 ml) of methyl triphenyl phosphonium bromide (5.36g, 15mmol), stirring for reaction for 1h, adding SM-1 (1.73g, 10mmol) into the reaction solution, continuing heating to room temperature for reaction, detecting after the reaction is finished, filtering, adding the filtrate into purified water (60 ml), extracting methyl tert-butyl ether (30 ml multiplied by 3), combining organic phases, concentrating and drying to obtain a compound I-1, wherein the obtained compound I-1 can be directly used in the next reaction.
The compound I-1 obtained above (in 10 mmol) was added to Sia 2 BH (6.82g, 12mmol) in THF (30 mL) is reacted at room temperature until the reaction of the raw material I-1 is completed, a proper amount of water and a 3M NaOH solution (21mL, 63mmol) are added, hydrogen peroxide (omega =30%,22.5mL, 60mmol) is added at the temperature of-5-2 ℃, the reaction is continued at room temperature until the reaction is completed, the pH of the solution is adjusted to be =10 by NaOH, then dichloromethane (30 mL x 3) is used for extraction, organic phases are combined, saturated sodium thiosulfate solution (30 mL x 3) is used for washing, saturated saline solution (30 mL) is used for washing, organic phase is subjected to pressure concentration and drying, and the target product I is prepared, wherein the yield is 92.2% and the purity is 98.68%.
Example 8
Under the protection of argon, controlling the temperature to be-5-0 ℃, adding a KHMDS/THF (16.5 ml,16.5 mmol) solution into THF (30 ml) of methyl triphenyl phosphonium bromide (5.36g, 15mmol), stirring for reacting for 1h, adding SM-1 (1.73g, 10mmol) into the reaction solution, continuing to rise to room temperature for reaction, detecting after the reaction is finished, filtering, pouring the filtrate into purified water (50 ml), extracting dichloromethane (30 ml multiplied by 3), combining organic phases, concentrating, and drying to obtain a compound I-1, wherein the obtained compound I-1 can be directly used in the next reaction.
Adding the compound I-1 (calculated by 10 mmol) obtained above into a THF (30 mL) solution of borane-N, N-dimethylaniline (1.63g, 12mmol), reacting at room temperature until the reaction of the raw material I-1 is completed, adding a proper amount of water and a 3M NaOH solution (13.3 mL, 40mmol), adding hydrogen peroxide (omega =30%,15mL, 40mmol) at the temperature of-5 to-2 ℃, continuing to react at room temperature until the reaction is completed, adjusting the pH of the solution to be 10 by using NaOH, then extracting by using dichloromethane (30 mL x 3), combining organic phases, washing by using a saturated sodium thiosulfate solution (30 mL x 3), washing by using a saturated saline solution (30 mL), concentrating by using organic phase under reduced pressure, and drying to obtain the target product I, wherein the yield is 92.5% and the purity is 98.72%.
Example 9
Under the protection of argon, controlling the temperature to be-5-0 ℃, adding a KHMDS/THF (16.5 ml,16.5 mmol) solution into THF (30 ml) of methyl triphenyl phosphonium bromide (5.36g, 15mmol), stirring for reacting for 1h, adding SM-1 (1.73g, 10mmol) into the reaction liquid, continuing to rise to room temperature for reaction, after the detection reaction is finished, pouring the reaction liquid into purified water (50 ml), extracting dichloromethane (30 ml multiplied by 3), combining organic phases, concentrating, and drying to obtain a compound I-1, wherein the obtained compound I-1 can be directly used in the next reaction.
Adding the compound I-1 (calculated by 10 mmol) obtained in the previous step into a THF (30 mL) solution of borane-N, N-dimethylaniline (1.63g, 12mmol), reacting at room temperature until the reaction of the raw material I-1 is completed, adding a proper amount of water and a 3M NaOH solution (14.7mL, 44mmol), adding hydrogen peroxide (omega =30%,15mL, 40mmol) at the temperature of-5 to-2 ℃, continuing to react at room temperature until the reaction is completed, adjusting the pH of the solution to be =10 by using NaOH, then extracting by using dichloromethane (30 mL × 3), combining organic phases, washing by using a saturated sodium thiosulfate solution (30 mL × 3), washing by using a saturated saline solution (30 mL), concentrating by using an organic phase under reduced pressure, and drying to obtain the target product I, wherein the yield is 93.1% and the purity is 98.80%.

Claims (10)

1. A preparation method of 7-ethyl tryptophol comprises the following steps:
step 1, under the protection of inert gas, SM-2 firstly reacts under alkaline conditions, then SM-1 is added for continuous reaction, and a compound I-1 is prepared;
step 2, adding the compound I-1 into a THF solution of a boron reagent for reaction, and reacting with hydrogen peroxide under an alkaline condition to obtain a compound I;
the reaction route is as follows:
Figure FDA0003126609150000011
wherein X in SM-2 is one of Br and I.
2. The preparation method according to claim 1, comprising the following steps:
step 1, controlling the temperature T under the protection of inert gas 1 Adding alkali/organic solvent A solution into organic solvent A of SM-2 for reaction, adding SM-1 into the reaction solution, heating to room temperature, and continuing the reaction to obtain a compound I-1;
step 2, adding the compound I-1 into THF solution of boron reagent, reacting at room temperature until the raw material I-1 completely reacts, adding a proper amount of water and inorganic alkali solution, and controlling the temperature T 2 Adding hydrogen peroxide, heating to room temperature and continuing to react to obtain the compound I.
3. The method of claim 1 or 2, wherein the base in step 1 is selected from t-BuOK, KHMDS, and NaHMDS.
4. The process according to claim 1 or 2, wherein the molar ratio of compounds SM-1 to SM-2 and base in step 1 is 1: 1.2-2.5: 1.2 to 3.0.
5. The method of claim 2, wherein the reaction temperature T in step 1 is 1 Is-10 to 10 ℃.
6. The method according to claim 2, wherein the organic solvent A in step 1 is one selected from tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and diethyl ether.
7. The method of claim 1 or 2, wherein the boron reagent in step 2 is selected from BH 3 ·Me 2 S、9-BBN、Sia 2 BH. borane-N, N-dimethylaniline.
8. The preparation method according to claim 1 or 2, wherein the feeding molar ratio of the compound I-1 to the boron reagent and hydrogen peroxide in the step 2 is 1:1.1 to 1.5:3.0 to 6.0.
9. The method according to claim 2, wherein the inorganic base in step 2 is selected from one of NaOH and KOH.
10. The method according to claim 2, wherein the feeding molar ratio of the inorganic base to the hydrogen peroxide in the step 2 is 1-1.1: 1.
CN202110690746.XA 2021-06-22 2021-06-22 Preparation method of 7-ethyl tryptophol Pending CN115504923A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110690746.XA CN115504923A (en) 2021-06-22 2021-06-22 Preparation method of 7-ethyl tryptophol

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110690746.XA CN115504923A (en) 2021-06-22 2021-06-22 Preparation method of 7-ethyl tryptophol

Publications (1)

Publication Number Publication Date
CN115504923A true CN115504923A (en) 2022-12-23

Family

ID=84499484

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110690746.XA Pending CN115504923A (en) 2021-06-22 2021-06-22 Preparation method of 7-ethyl tryptophol

Country Status (1)

Country Link
CN (1) CN115504923A (en)

Similar Documents

Publication Publication Date Title
CN111704573B (en) Preparation method of rabeprazole chloride and intermediate thereof
CN113234004A (en) Novel preparation process of brivaracetam
WO2008041734A1 (en) Tertiary alkyl ester of oxodibenzoxepin acetic acid
CN115504923A (en) Preparation method of 7-ethyl tryptophol
CN113666860B (en) Preparation method of 7-ethyl tryptol
CN111675653A (en) Preparation method and application of impurities of 4-aminoquinoline compound
CN105622380B (en) Preparation method of apremilast and intermediate thereof
CN108503609B (en) Method for preparing optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -ketone
CN111533689B (en) 2,2' -biquinoline compound and one-pot preparation method thereof
WO2020118597A1 (en) Process for making 1- [ (3r, 4s) -4-cyanotetrahydropyran-3-yl] -3- [ (2-fluoro-6-methoxy-4-pyridyl) amino] pyrazole-4-carboxamide
CN114478837A (en) Preparation method of sugammadex sodium derivative
CN111675660B (en) Preparation method for synthesizing palbociclib intermediate and method for synthesizing palbociclib
CN111440181B (en) Dipyrazolo seven-membered oxygen heterocyclic compound containing quinoline structure and synthetic method thereof
CN114702425A (en) Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate
CN108358866B (en) Preparation method of febuxostat intermediate and application of febuxostat intermediate in preparation of febuxostat
CN115232054A (en) 7-ethyl tryptophol intermediate compound
CN113929612B (en) Preparation method of etodolac intermediate
CN113416142B (en) Preparation method of 5-ALA intermediate 5-bromolevulinate
CN111377867B (en) Intermediate for synthesizing 2- (1-alkyl-1H-pyrazol-4-yl) morpholine and preparation method and application thereof
CN113387791B (en) Method for synthesizing ivabradine hydrochloride key intermediate
CN110684000B (en) Process for preparing benzofuran derivatives
CN114736217B (en) Preparation method of toraseplug Mi Huange impurity
CN117447448A (en) Synthesis method of dabigatran etexilate intermediate
CN109836379B (en) Method for converting halogenated pyridine carboxylic acid into cyano-substituted pyridine carboxylic acid
CN117800924A (en) Synthesis method of PARP inhibitor intermediate

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination