CN115583898A - Preparation method of aryl isothiocyanate - Google Patents
Preparation method of aryl isothiocyanate Download PDFInfo
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- CN115583898A CN115583898A CN202210791874.8A CN202210791874A CN115583898A CN 115583898 A CN115583898 A CN 115583898A CN 202210791874 A CN202210791874 A CN 202210791874A CN 115583898 A CN115583898 A CN 115583898A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
- C07C331/16—Isothiocyanates
- C07C331/28—Isothiocyanates having isothiocyanate groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C335/22—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of aryl isothiocyanate. The aryl bromide and the cyanation reagent are used as raw materials to carry out cyanation reaction, aryl nitrile is obtained through a one-step method, and then aryl isothiocyanate is generated through reaction with a non-thiophosgene reagent. The preparation process of the invention does not need protection of acetyl protecting group, thus reducing reaction steps and greatly improving atom economy and total reaction yield; and a technical scheme for preparing aryl isothiocyanate by removing thiophosgene is provided in the reaction process, so that the method is more environment-friendly and is suitable for industrial large-scale production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of aryl isothiocyanate.
Background
Aryl isothiocyanates are important medical intermediates, and are widely used for preparing androgen receptor antagonists with thiohydantoin structures, such as Enzalutamide (Enzalutamide), apatamide (Apalutamide) and pramipexole (Pruxelutamide).
The compound of formula a is an intermediate for preparing pramipexole (Pruxelutamide), and the applicant discloses a preparation method thereof in CN103608333B, and the synthetic route is as follows:
in the reaction route, the compound 11 is used as a raw material, and the compound of the formula A is generated through multi-step reaction. In the preparation of compound 15, the corresponding amino group must be protected with acetyl group, followed by cyanation and deprotection. Finally, compound 15 reacts with thiophosgene to form the target product.
The above route has the following drawbacks: 1) Protection and deprotection of amino groups are needed in the reaction process, the reaction steps are long, the total yield is low (the total yield of the compound 15 obtained by carrying out bromination, amino protection, cyanation and deprotection on the compound 11 described in the paragraphs [0483] - [0493] in the specification is 75% multiplied by 85% multiplied by 80% multiplied by 90% = 45.9%), and the atom economy is poor; 2) Thiophosgene is not environment-friendly and is not beneficial to production amplification.
Clinical experimental results show that the prochloraz (pruxeutamide) can be used for treating the COVID-19, so that the defects in the prior art need to be overcome, and a route suitable for industrial production is provided for preparing an aryl isothiocyanate compound serving as an intermediate of the prochloraz, namely a compound in a formula A.
Disclosure of Invention
Problems to be solved by the invention
In order to solve the problems in the prior art, the invention provides a method for preparing aryl isothiocyanate, and the method adopts a one-step method to carry out cyanation reaction without protecting amino; and a technical scheme for preparing aryl isothiocyanate by removing thiophosgene is provided in the reaction process, so that the method is more environment-friendly.
Means for solving the problems
According to a first aspect of the present invention there is provided a process for the preparation of compound 15, said process comprising reacting compound 12 in the presence of a solvent and a cyanating reagent to form compound 15 according to the reaction equation:
preferably, the solvent is a polar organic solvent; the polar organic solvent is selected from any one or more of nitriles, sulfoxides, chain amides or cyclic amides, preferably one or more of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidone, and more preferably N, N-dimethylformamide.
Preferably, the cyanating reagent is selected from KCN, naCN, cuCN, zn (CN) 2 、Ni(CN) 2 、K 4 [Fe(CN) 6 ]Or K 3 [Fe(CN) 6 ]Any of these, cuCN is more preferable.
Preferably, the solvent is N, N-dimethylformamide and the cyanating agent is CuCN.
Preferably, the method comprises dropwise adding the compound 12 into a system of a solvent (preferably N, N-dimethylformamide) and a cyanating agent (preferably CuCN), and raising the temperature for reaction after the dropwise addition is finished.
Preferably, the temperature of the system is controlled in the dropping process; more preferably, the system temperature is 10-50 ℃, preferably 10-40 ℃ or 15-35 ℃, and even more preferably 20-30 ℃.
Preferably, the molar amount of the cyanation agent is 1.0 to 1.5 times, preferably 1.1, 1.2, 1.3 or 1.4 times, and more preferably 1.1 times that of compound 12.
Preferably, the temperature of the reaction is 110 to 140 ℃, preferably 110 to 130 ℃, further preferably 120 to 130 ℃.
Preferably, the method further comprises a step of post-processing, the step of post-processing comprising: adding an organic phase solvent and a water phase solvent into the reaction system, extracting, washing and concentrating the organic phase to obtain the organic phase-change material. Preferably, the organic phase solvent is a chlorinated hydrocarbon, preferably dichloromethane; the aqueous phase solvent is water.
Preferably, the post-processing step comprises: adding an organic phase solvent and a water phase solvent into the reaction system, extracting, washing, concentrating the organic phase, and pulping to obtain the organic phase-modified chitosan. Preferably, the organic phase solvent is a chlorinated hydrocarbon, preferably dichloromethane; the aqueous phase solvent is ammonia water; the beating is done with an alkane, preferably n-heptane.
By adjusting the parameters of the charging sequence, the charging mode, the dripping temperature, the reaction temperature and the like in the step of reaction, the compound 12 can obtain the compound 15 through one-step reaction, and the yield of the step of reaction is greatly improved. In addition, the inventor optimizes the post-treatment step, adopts the processes of adding ammonia water for extraction and pulping, and greatly improves the purity of the product on the premise of ensuring high yield.
Further, in the method for preparing the compound 15, the method for preparing the compound 12 comprises the following steps: compound 11 is reacted in the presence of an organic solvent and a brominating reagent to produce compound 12, the reaction equation is as follows:
preferably, the organic solvent is one or a combination of more of chain or cyclic amides, preferably one or a combination of two of N, N-dimethylformamide and N, N-dimethylacetamide, and more preferably N, N-dimethylformamide.
Preferably, the brominating reagent is N-bromosuccinimide (NBS), 1, 3-dibromo-5, 5-Dimethylhydantoin (DBH), 3, 5-Dibromobenzaldehyde (DBBA), N-bromophthalimide (NBP), or 1,3, 5-tribromo-1, 3, 5-triazine-2, 4, 6-Trione (TBCA).
Preferably, the method comprises adding dropwise a brominating reagent (preferably NBS) or a system of a brominating reagent and an organic solvent (preferably a system of NBS and N, N-dimethylformamide) to a system of the compound 11 and an organic solvent (preferably N, N-dimethylformamide), and raising the temperature for reaction after the completion of the dropwise addition.
Preferably, the temperature of the system is controlled in the dropping process; more preferably, the system temperature is-5 to 5 ℃, further preferably 0 ℃ (such as ice bath).
Preferably, the method further comprises a step of post-processing, the step of post-processing comprising: and adding an aqueous solution of a quenching agent and an organic phase solvent into the reaction system, extracting, and concentrating the organic phase to obtain the organic phase. Preferably, the quencher is a bisulfite salt, preferably sodium bisulfite; the organic phase solvent is an ester, preferably ethyl acetate.
In CN103608333B, the dropping process of the reaction is not temperature-controlled and is carried out at room temperature, and the final yield of the reaction is only 75%. In the subsequent treatment step, ether was added for dilution, and the mixture was washed with brine, but excess NBS was not quenched, and if the cyanation reaction was carried out without purifying compound 12, excess NBS may remain in the cyanation reaction to affect the yield.
Further, the specific steps of the method for preparing the compound 15 are as follows:
adding N, N-dimethylformamide and a compound 11 into a reaction bottle, stirring and dissolving, dropwise adding an N, N-dimethylformamide solution of NBS under an ice bath condition, and naturally heating to room temperature for reaction after dropwise adding is finished; after the reaction is finished, dropwise adding sodium bisulfite aqueous solution, extracting by ethyl acetate, collecting an organic phase, and concentrating under reduced pressure to obtain a compound 12;
adding CuCN and N, N-dimethylformamide into a reaction bottle, stirring, dropwise adding the compound 12 obtained in the step into the reaction bottle, controlling the system temperature and the dropwise adding time, and heating to react after the dropwise adding is finished; cooling to room temperature after the reaction is finished, adding an ammonia water solution and dichloromethane, stirring, extracting, collecting a dichloromethane layer, washing the dichloromethane layer by using saturated saline solution, collecting an organic layer, concentrating to obtain a crude product, and pulping the crude product by using n-heptane to obtain a compound 15;
preferably, the reaction temperature, reaction time, molar ratio of the reaction reagents, and the like in the above-mentioned specific steps are as defined in the aforementioned method for producing compound 12 and compound 15.
According to a second aspect of the invention, there is provided a process for the preparation of a compound of formula a, which process comprises: reacting the compound 15 with a non-thiophosgene reagent in a solvent or a non-solvent to generate a compound shown in a formula A, wherein the reaction equation is as follows:
preferably, the compound 15 can be prepared by the method described in the first aspect.
Preferably, the non-thiophosgene reagent is any one of N, N' -thiocarbonyldiimidazole, carbon disulfide, N-dimethylthiocarbamoyl chloride or phenyl thiocarbamate.
According to a third aspect of the present invention, there is provided a further process for the preparation of a compound of formula A, which process comprises reacting compound 12 in the presence of a solvent and a cyanating reagent to form compound 15, and reacting compound 15 with a non-thiophosgene reagent in the presence of a solvent or a non-solvent to form a compound of formula A, the reaction equation being as follows:
preferably, the compound 15 can be prepared by the method of the first aspect.
Preferably, the non-thiophosgene reagent refers to N, N' -thiocarbonyldiimidazole, carbon disulfide, N-dimethylthiocarbamoyl chloride or phenyl thiocarbamate, and the reaction equation is as follows:
in addition, the applicant found in previous studies that by controlling the reaction conditions, compound 15 can form a new ring closure product with non-thiophosgene reagent: a compound represented by formula I or a compound represented by formula II. Therefore, the present invention also provides the use of compound 15 in the preparation of a compound of formula I or a compound of formula II, wherein said compound 15 is prepared by the method of the first aspect.
Taking a compound 15 as a raw material, taking N, N' -thiocarbonyl diimidazole as a reaction reagent, and reacting in a reaction system of organic base and organic solvent to generate a compound shown in a formula I, wherein the reaction equation is as follows:
preferably, the compound 15 can be prepared by the method described in the first aspect.
Preferably, the organic base is a nitrogen-containing organic base; preferably, the nitrogen-containing organic base is any one or more of N, N-Diisopropylethylamine (DIPEA), N-diisopropylaniline, 4-Dimethylaminopyridine (DMAP), lutidine, imidazole, triethylamine or pyridine, preferably triethylamine and/or DMAP.
Preferably, the organic solvent is a halogenated hydrocarbon, an aromatic hydrocarbon, a C2-C6 nitrile, preferably toluene and/or acetonitrile.
Preferably, the molar amount of the N, N' -thiocarbonyldiimidazole is 1 to 3 times, preferably 2 times that of the compound 15.
Preferably, the molar amount of the organic base is 0.1 to 5 times, preferably 3 times, the amount of the compound 15.
Preferably, the temperature of the reaction is from 0 ℃ to below the boiling point, preferably from 40 ℃ to below the boiling point, for example from 50 to 90 ℃, from 50 to 80 ℃, from 60 to 70 ℃ or from 80 to 90 ℃.
Similarly, compound 15 is used as raw material, carbon disulfide is used as reaction reagent, and the reaction is carried out in the reaction system of organic base and organic solvent, so as to generate the compound shown in formula II, wherein the reaction equation is as follows:
preferably, the compound 15 can be prepared by the method described in the first aspect.
Preferably, the organic base is triethylamine, pyridine, N-Diisopropylethylamine (DIPEA), triethylenediamine (DABCO), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 1, 8-diazohetero-bis-spiro [5.4.0] undec-7-ene (DBU), 4-Dimethylaminopyridine (DMAP), N-methylmorpholine, tetramethylethylenediamine or a mixture thereof, more preferably triethylenediamine.
Preferably, the organic solvent is an alkyl ketone, preferably the alkyl ketone is acetone, butanone or methyl isobutyl ketone, preferably acetone.
Preferably, the molar ratio of carbon disulphide to compound 15 is 1-3 times, such as 1.2, 1.5 or 2.0 times, more preferably 1.2 times.
Preferably, the molar ratio of the organic base to the compound 15 is 0.1 to 1 times, more preferably 0.2 to 0.8 times (e.g., 0.2,0.4,0.6, 0.8), and still more preferably 0.4 to 0.5 times.
The compound shown in the formula I or the compound shown in the formula II can be used as an impurity generated in the preparation process of the compound shown in the formula A, is used for controlling the quality of a target product of the compound shown in the formula A, monitoring the content of the compound shown in the formula I or the compound shown in the formula II in the target product, and evaluating the quality of the target product. Therefore, the invention also provides the application of the compound shown in the formula I or the compound shown in the formula II or the preparation method thereof in the product quality control of the compound shown in the formula A.
According to a fourth aspect of the present invention, there is provided a further process for the preparation of a compound of formula a, said process comprising the steps of:
wherein, P is an amino protecting group;
1) Compound 15 is reacted in the presence of thiocyanate and amino protecting agent to produce compound 15-1;
preferably, the compound 15 can be prepared by the method of the first aspect;
preferably, the thiocyanate is any one of ammonium thiocyanate, sodium thiocyanate, potassium thiocyanate, magnesium thiocyanate or manganese thiocyanate, and preferably ammonium thiocyanate;
preferably, the amino protecting group is any one of alkoxycarbonyl, acyl or alkyl; further, the alkoxycarbonyl group in the amino protecting group may be substituted or unsubstituted with a substituent which may be an aryl group, an alkenyl group or an alkylsilyl group; the alkyl group in the amino protecting group may be substituted or unsubstituted by a substituent which may be an aryl group or an aryl group substituted by an alkoxy group; furthermore, the alkoxycarbonyl is any one of carbobenzoxy Cbz, tert-butyloxycarbonyl Boc, fluorenylmethyloxycarbonyl Fmoc, allyloxycarbonyl Alloc or trimethylsiloxyethoxycarbonyl Teoc; the acyl is any one of phthaloyl Pht, tosyl Tos, trifluoroacetyl Tfa or benzoyl Bz, preferably benzoyl Bz; the alkyl is any one of trityl Trt,2, 4-dimethoxy benzyl Dmb, p-methoxy benzyl Pmb or benzyl Bn;
2) Removing the amino protecting group from the compound 15-1 to generate a compound 15-2;
one of ordinary skill in the art can use different deprotection group systems according to the different protection groups; preferably, compound 15-1 can be deprotected from the amino protecting group in a system of base and solvent; the base is an inorganic base, preferably an alkali metal hydroxide, more preferably sodium hydroxide or potassium hydroxide; the solvent is an alcohol solvent, preferably methanol, ethanol or isopropanol and the like;
3) Removing ammonia gas from the compound 15-2 to generate a compound shown in the formula A;
ammonia can be removed by heating in an organic solvent with a high boiling point, for example, toluene, xylene, chlorobenzene, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide or N-methylpyrrolidone; or adding acidic salt (one or more of sodium bisulfate, potassium bisulfate, sodium bisulfite, potassium bisulfite, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen oxalate, potassium hydrogen oxalate, etc.) into a mixed system of organic solvent and water to perform catalytic reaction to remove ammonia gas.
According to a fifth aspect of the present invention, there is provided another process for preparing a compound of formula a, the process comprising: compound 12 is reacted in the presence of a solvent and a cyanating agent to produce compound 15, and compound 15 is reacted by the method described in the fourth aspect to produce the compound represented by formula A, the reaction equation being as follows:
wherein, P is an amino protecting group.
Preferably, the compound 15 is prepared by the method of the first aspect.
ADVANTAGEOUS EFFECTS OF INVENTION
Compared with the prior art, the invention has the following advantages:
1) The compound 12 is used as a raw material, and a direct cyanation method is adopted to prepare a compound 15 through one-step reaction; the protection of acyl protecting group is abolished, the reaction steps are reduced, and the atom economy is greatly improved; by controlling the conditions of feeding sequence, feeding mode, feeding temperature, reaction temperature, post-treatment and the like in the bromination and cyanation two-step reaction, the total yield of the reaction can reach 80 percent and is far higher than that in CN103608333B (the total yield of the bromination, acyl protection, cyanation and deprotection four-step reaction is 45.9 percent); particularly, the post-treatment of the cyanation reaction adopts the steps of ammonia water extraction washing and n-heptane hot pulping, so that a large amount of impurities are removed, and the product purity is greatly improved on the premise of ensuring high yield.
2) The compound of the formula A is prepared by adopting reagents such as N, N' -thiocarbonyl diimidazole, carbon disulfide, N-dimethylthiocarbamoyl chloride, phenyl thiocarbamate or thiocyanate and the like, so that thiophosgene is replaced, and the defects of high environmental pollution and unfavorable production amplification of the thiophosgene are overcome. Meanwhile, the invention also provides a new ring closure product which can be generated by the compound 15 and reagents such as N, N' -thiocarbonyl diimidazole or carbon disulfide and the like under specific reaction conditions, and the ring closure product or the preparation method thereof can be applied to the quality control of the compound product in the formula A.
Drawings
FIG. 1 is an HPLC chromatogram of the compound prepared in example 1 of the present invention.
FIG. 2 is an LC-MS spectrum of the compound prepared in example 2 of the present invention.
FIG. 3 is a NMR chart of the compound prepared in example 2 of the present invention.
FIG. 4 is an LC-MS spectrum of the compound prepared in example 3 of the present invention.
Detailed Description
The "compound of formula a", or "aryl isothiocyanate compound of formula a" in the present invention each means a compound having the following structure, which is an intermediate of prochloraz (Pruxelutamide).
The invention may be further understood by reference to the following examples, which, however, are not to be construed as limiting the invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the invention as described herein and claimed below.
The HPLC detection method for compound 15 is as follows:
a chromatographic column: c18 150X 4.6mm; column temperature: 25 ℃; flow rate: 1.0mL/min; sample introduction amount: 5 mu L of the solution;
detection wavelength: 220nm;
mobile phase: binary mobile phase system: mobile phase a was 0.02V% aqueous acetic acid; the mobile phase B is acetonitrile;
and (3) an elution mode: gradient elution (during gradient elution, the maximum volume percentage of mobile phase a is 90%, and the minimum volume percentage is 0%).
EXAMPLE 1 preparation of Compound 15
Adding 60ml of organic solvent N, N-dimethylformamide and 12g of compound shown in formula 11 into a reaction bottle, stirring for dissolving, dropwise adding 40ml of N, N-dimethylformamide solution of NBS (NBS is 1.05 times of the molar weight of the compound shown in formula 11) under an ice bath condition, naturally heating to room temperature after the dropwise adding is finished, and reacting for 16-24h; after the reaction, an aqueous solution of sodium bisulfite was added dropwise to quench the excess NBS, and the mixture was extracted with ethyl acetate (3X 60 ml), and the organic phase was collected and concentrated under reduced pressure to give compound 12 as an oily substance.
Adding CuCN (which is 1.1 times of the molar weight of the compound shown in the formula 11) and 50ml of N, N-dimethylformamide into a reaction bottle, stirring, dropwise adding all the compound 12 obtained in the step into the reaction bottle at 20-30 ℃, controlling the dropwise adding time to be 1-2h, and heating to 120-130 ℃ after the dropwise adding is finished to react for 6-8h; after the reaction is finished, cooling to room temperature, adding 50ml of ammonia water solution and dichloromethane, stirring and extracting (60 ml multiplied by 2), collecting a dichloromethane layer, washing the dichloromethane layer by adopting saturated saline solution, collecting an organic layer, concentrating until no fraction is distilled off, obtaining a crude product, stirring and pulping the crude product by adopting 60ml of n-heptane at 40-50 ℃ for 6-8h, filtering and drying to obtain 10.8g of a compound 15 (the purity is 99.5% by HPLC area normalization method, the retention time is 8.39min, the HPLC map is shown in figure 1), and the yield is 80.0% (calculated by the material amount of the compound 11, and the purity of the compound 15 is calculated by 100%).
The applicant does not optimize the post-treatment in the earlier stage, and methylene dichloride and water are added in the post-treatment process for extraction and concentration to obtain the product with the purity of only 83.3 percent and the yield basically same as that of the method. Therefore, the post-treatment adopts ammonia water combined with n-heptane pulping, so that the product purity can be obviously improved, and the product loss is less.
Example 2
Compound 15 (1.0g, 4.9mmol), N' -thiocarbonyldiimidazole (1.75g, 9.8mmol), toluene 10ml and triethylamine (1.49g, 14.7mmol) are added into a reaction bottle, stirred and dissolved, the temperature is increased to 80 ℃ for reaction for 6 hours, a sample is taken for TLC monitoring, the reaction is completed, the heating is stopped, and the temperature is reduced to the room temperature.
Toluene was removed by rotary evaporation and purified by column chromatography (PE: EA =2 f = 0.2-0.3), so that the compound shown in the formula I (1.13 g) is obtained with a yield of 73.4%.
LC-MS:m/z 295.05[M+1] + ；
1 H NMR(400MHz,DMSO-d6):δ8.73(s,1H),8.41(d,J＝8.4Hz,1H),8.30(d,J＝8.4Hz,1H),8.12(s,1H),7.28(s,1H)。
Example 3
Adding compound 15 (2.0 g, 10mmol), carbon disulfide (0.91g, 12mmol), acetone 20ml and triethylene diamine 0.5ml (0.45 times of compound 15 mol weight) into a reaction bottle, stirring for dissolving, heating to 40-50 ℃ for reacting for 6-8h, sampling, monitoring by TLC, stopping heating, and cooling to room temperature.
Acetone was removed by rotary evaporation and purified by column chromatography (PE: EA =2 f ＝0.2-0.3)，Obtaining the compound shown in the formula II.
LC-MS:m/z 258.92[M-1] - 。
Example 4
A compound of formula A, wherein P is benzoyl, is prepared as described above. The method comprises the following specific steps:
1) Reacting the compound 15 in the presence of ammonium thiocyanate and benzoyl chloride, and carrying out post-treatment to obtain a compound 15-1;
2) Removing benzoyl from the compound 15-1 under the condition that sodium hydroxide is used as alkali and methanol is used as a solvent, and performing post-treatment to obtain a compound 15-2;
3) And heating the compound 15-2 in a solvent system of chlorobenzene to remove ammonia gas, and generating a target product, namely the compound shown as the formula A.
Claims (12)
1. A method of making compound 15, the method comprising: compound 12 is reacted in the presence of a solvent and a cyanating reagent to form compound 15,
2. the method of claim 1, wherein:
the solvent is a polar organic solvent, the polar organic solvent is preferably any one or combination of more of nitriles, sulfoxides, chain amides or cyclic amides, and more preferably any one or combination of more of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidone;
the cyanation reagent is selected from KCN, naCN, cuCN, zn (CN) 2 、Ni(CN) 2 、K 4 [Fe(CN) 6 ]Or K 3 [Fe(CN) 6 ]Any one of them.
3. The method of claim 2, wherein:
the solvent is N, N-dimethylformamide, and the cyanation reagent is CuCN.
4. The method according to any one of claims 1-3, wherein:
the method comprises the following steps: dropwise adding the compound 12 into a system of the solvent and the cyanation reagent, and heating for reaction after dropwise adding is finished;
preferably, the temperature of the system is controlled in the dropping process;
more preferably, the system temperature is 10 to 50 ℃, further preferably 20 to 30 ℃.
5. The method of claim 4, wherein:
the molar amount of the cyanating agent is 1.0 to 1.5 times, preferably 1.1, 1.2, 1.3 or 1.4 times, more preferably 1.1 times that of the compound 12;
preferably, the temperature of the reaction is 110 to 140 ℃, further preferably 120 to 130 ℃.
6. The method according to claim 4 or 5, characterized in that:
the method further comprises a step of post-processing, the step of post-processing comprising: adding an organic phase solvent and a water phase solvent into the reaction system, extracting, washing and concentrating an organic phase to obtain the organic phase-change material; preferably, the organic phase solvent is a chlorinated hydrocarbon, preferably dichloromethane; the aqueous phase solvent is water;
preferably, the post-processing step comprises: adding an organic phase solvent and a water phase solvent into the reaction system, extracting, washing, concentrating the organic phase, and pulping to obtain the organic phase-modified starch; preferably, the organic phase solvent is a chlorinated hydrocarbon, preferably dichloromethane; the aqueous phase solvent is ammonia water; the beating is done with an alkane, preferably n-heptane.
7. The method of claim 1, wherein:
the preparation method of the compound 12 comprises the following steps: compound 11 reacts in the presence of an organic solvent and a brominating reagent to produce compound 12,
preferably, the organic solvent is one or a combination of more of chain or cyclic amides, preferably one or a combination of two of N, N-dimethylformamide and N, N-dimethylacetamide;
preferably, the brominating reagent is NBS, DBH, DBBA, NBP or TBCA;
more preferably, the organic solvent is N, N-dimethylformamide and the brominating agent is NBS;
preferably, the method comprises: dripping the brominating reagent or the system of the brominating reagent and the organic solvent into the system of the compound 11 and the organic solvent, and heating for reaction after dripping is finished;
preferably, the temperature of the system is controlled in the dropping process; more preferably, the system temperature is-5 to 5 ℃, and still more preferably 0 ℃.
8. The method according to claims 1-7, characterized in that:
the method comprises the following specific steps:
adding N, N-dimethylformamide and a compound 11 into a reaction bottle, stirring and dissolving, dropwise adding an N, N-dimethylformamide solution of NBS under an ice bath condition, and naturally heating to room temperature for reaction after dropwise adding is finished; after the reaction is finished, dropwise adding sodium bisulfite aqueous solution, extracting by ethyl acetate, collecting an organic phase, and concentrating under reduced pressure to obtain a compound 12;
adding CuCN and N, N-dimethylformamide into a reaction bottle, stirring, dropwise adding the compound 12 obtained in the step into the reaction bottle, controlling the dropwise adding time and temperature, and raising the temperature for reaction after the dropwise adding is finished; and after the reaction is finished, cooling to room temperature, adding ammonia water and dichloromethane, stirring, extracting, collecting a dichloromethane layer, washing the dichloromethane layer with saturated saline solution, collecting an organic layer, concentrating to obtain a crude product, and pulping the crude product with n-heptane to obtain the compound 15.
9. A process for preparing an aryl isothiocyanate compound of formula a comprising the steps of:
wherein, P is an amino protecting group;
1) Compound 15 is reacted in the presence of thiocyanate and an amino protecting agent to form compound 15-1; preferably, said compound 15 is prepared by a process according to any one of claims 1-8;
2) Removing the amino protecting group from the compound 15-1 to generate a compound 15-2;
3) Removing ammonia gas from the compound 15-2 to generate a compound shown in the formula A;
preferably, the thiocyanate is any one of ammonium thiocyanate, sodium thiocyanate, potassium thiocyanate, magnesium thiocyanate or manganese thiocyanate, and more preferably ammonium thiocyanate;
preferably, the amino protecting group is any one of alkoxycarbonyl, acyl or alkyl; more preferably, the alkoxycarbonyl is any one of benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl or trimethylsiloxycarbonyl; the acyl is any one of phthaloyl, p-toluenesulfonyl, trifluoroacetyl or benzoyl, and is preferably benzoyl; the alkyl is any one of trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl or benzyl.
10. A method of preparing an aryl isothiocyanate compound of formula a, the method comprising: reacting compound 12 in the presence of a solvent and a cyanating reagent to form compound 15, reacting compound 15 by the method according to claim 9 to form a compound of formula a,
preferably, said compound 15 is prepared by a process according to any one of claims 1-8.
11. Use of compound 15 in the preparation of a compound having a structure according to formula I or formula II, wherein compound 15 is prepared by a method according to any one of claims 1-8:
12. a method of preparing a compound of formula II, the method comprising: taking a compound 15 as a raw material, taking carbon disulfide as a reaction reagent, reacting in the presence of organic base and organic solvent to generate a compound shown in a formula II,
preferably, said compound 15 is prepared by a process according to any one of claims 1-8;
preferably, the organic base is at least one of triethylamine, pyridine, N-diisopropylethylamine, triethylenediamine, 1, 5-diazabicyclo [4.3.0] non-5-ene, 1, 8-diazohetero-bis-spiro [5.4.0] undec-7-ene, 4-dimethylaminopyridine, N-methylmorpholine, tetramethylethylenediamine, more preferably triethylenediamine;
preferably, the organic solvent is an alkyl ketone, more preferably acetone, butanone or methyl isobutyl ketone, further preferably acetone;
preferably, the molar amount of carbon disulphide is 1-3 times, more preferably 1.2, 1.5 or 2.0 times, even more preferably 1.2 times that of the compound 15;
preferably, the molar amount of the organic base is 0.1 to 1 time, more preferably 0.2 to 0.8 time, and still more preferably 0.4 to 0.5 time that of the compound 15.
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| CN102482230A (en) * | 2009-09-10 | 2012-05-30 | 童友之 | Androgen receptor antagonists and uses thereof |
| CN105308025A (en) * | 2013-05-20 | 2016-02-03 | 杜邦公司 | Solid forms of fungicidal pyrazoles |
| WO2021133894A1 (en) * | 2019-12-23 | 2021-07-01 | Biogen Ma Inc. | Btk inhibitors |
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| CN102482230A (en) * | 2009-09-10 | 2012-05-30 | 童友之 | Androgen receptor antagonists and uses thereof |
| CN105308025A (en) * | 2013-05-20 | 2016-02-03 | 杜邦公司 | Solid forms of fungicidal pyrazoles |
| WO2021133894A1 (en) * | 2019-12-23 | 2021-07-01 | Biogen Ma Inc. | Btk inhibitors |
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