CN107759618B - Preparation method of brinzolamide and intermediate thereof - Google Patents
Preparation method of brinzolamide and intermediate thereof Download PDFInfo
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Abstract
The inventionDiscloses a preparation method of brinzolamide and intermediates thereof. The preparation method of the brinzolamide intermediate shown as the compound C comprises the following steps: under the anhydrous condition, in an organic solvent and in the presence of tertiary amine, carrying out condensation reaction on the compound B and an orthoester compound at 70-80 ℃; wherein the orthoesters compound is one or more of trimethyl orthoacetate, triethyl orthoacetate and trimethyl orthobenzoate. The preparation method of the invention uses tertiary amine as a catalyst to carry out condensation reaction, greatly shortens the reaction time of the amino protection step, reduces the dosage of a protection reagent, reduces the reaction temperature, and improves the product yield and purity; and the acid and alkali dosage used in the post-treatment process is reduced, the burning residue of the product is reduced, the operation is simplified, and the method is more suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of brinzolamide and an intermediate thereof.
Background
Brinzolamide (Brinzolamide), the chemical name of which is R- (+) -4-ethylamino-2- (3-methoxypropyl) -3, 4-dihydro-2H-thieno [3,2-e ] -1, 2-thiazine-6-sulfanilamide-1, 1-dioxide, has the structure shown in formula A. Brinzolamide is a pharmaceutically active component for treating primary and secondary open-angle glaucoma and ocular hypertension, and also for preventing and treating increased intraocular pressure after laser surgery, which Brinzolamide can be used as a single treatment drug for patients who have no effect on β -blocking agents or use contraindications, or as a synergistic treatment drug for β -blocking agents.
Dean et al, 1995, for the first time, disclosed in US5378703 a complete preparation method of brinzolamide, which was synthesized from 3-acetylthiophene through 12 steps of carbonyl protection, sulfonamidation, deprotection, carbonyl α -hydrobromination, reduction-ring closure, N-alkylation, hydroxyl protection, methoxy substitution, secondary sulfamidation, oxidation, asymmetric reduction, ethylation, and the like, and laid the foundation for further exploration of its preparation method, and its synthetic route is shown below.
In 1999, Conrow proposed a synthetic route using 2, 5-dichloro-3-acetylthiophene as starting material (see R.E. Conrow, et al, Organic Process Research & Development1999,3, 114-120), which is shown below, starting from 2, 5-dichloro-3-acetylthiophene, via 8-step reactions such as thioetherification, sulfoamination, carbonyl α -hydrobromide, asymmetric reduction-ring closure, N-alkylation, secondary sulfoamination, amine protection and ethylation to form brinzolamide, which is shown below.
Patent WO2008062463 discloses an optimized synthesis process of brinzolamide, which is based on a synthesis route disclosed in patent US5378703 and is fused with a preparation method proposed by Conrow, a chiral hydrogenation reagent (+) -IpcBCl is directly used for a reduction ring-closing reaction, and brining out from 3-acetylthiophene, and then synthesizing the brinzolamide through 8 steps of carbonyl protection, sulfoamination, deprotection, carbonyl α -hydrobromination, asymmetric reduction-ring-closing, N-alkylation, secondary sulfoamination, ethylation and the like, wherein the synthesis route is shown as follows.
And finally, reacting the compound B shown as the following under certain conditions to generate the brinzolamide shown as the formula A in the three synthetic routes.
The preparation method proposed by Conrow is simple, namely amino protection is performed firstly, sulfonate is generated again, and finally ethylamine is used for aminolysis, three steps are continuously fed, column chromatography purification is not needed for aftertreatment, a large amount of solvent is not needed to be distilled, and the route is reasonable and is shown in the following formula.
However, the synthetic route still has some problems in industrial production, such as long reaction time of the amino protection step, high reaction temperature, large consumption of reaction reagents, large consumption of post-treatment reagents, easy overproof inorganic salt residue of products, pending further improvement of reaction yield and purity, complex reaction operation and the like, so that the development of a preparation method of brinzolamide more suitable for industrial production has important significance.
Disclosure of Invention
The invention aims to solve the technical problems that in the existing preparation method of brinzolamide, the reaction time of an amino protection step is long, the reaction temperature is high, the consumption of reaction reagents is large, the consumption of post-treatment reagents is large, the residual inorganic salt of a product is easy to exceed the standard, the reaction yield and purity are required to be further improved, the reaction operation is complicated and the like when the brinzolamide is synthesized by a compound B, so that the preparation method of the brinzolamide and the intermediate thereof synthesized by the compound B is provided.
The present invention solves the above technical problems by the following technical solutions.
One of the technical schemes of the invention is as follows:
the invention provides a preparation method of a brinzolamide intermediate shown as a compound C, which comprises the following steps: under the anhydrous condition, in an organic solvent and in the presence of tertiary amine, carrying out condensation reaction on a compound B (S) -4-hydroxy-2- (3-methoxypropyl) -3, 4-dihydro-thieno [3,2-e ] -1, 2-thiazine-6-sulfonamide-1, 1-dioxide and an orthoester compound at 70-80 ℃; wherein the orthoesters compound is one or more of trimethyl orthoacetate, triethyl orthoacetate and trimethyl orthobenzoate;
the anhydrous condition is conventional in the field and can be realized by adopting a conventional treatment mode in the field, and the anhydrous condition of the reaction is preferably controlled by replacing the gas in the system by inert gas or nitrogen and performing a water removal operation on all reagents participating in the reaction.
The organic solvent is an organic solvent conventionally used in condensation reaction in the field, such as alcohols, ethers, esters, aromatic hydrocarbons, halogenated alkanes, nitriles, DMSO or DMF, or a mixture of any two or more of the above, the invention particularly preferably adopts a nitrile solvent or an ether solvent, and the nitrile solvent preferably adopts acetonitrile.
The dosage of the organic solvent is the dosage of the conventional solvent for condensation reaction in the field, and the ratio of the dosage of the organic solvent to the volume mass of the compound B is particularly preferably 5-15 mL/g, and further preferably 8-10 mL/g.
The tertiary amine is aliphatic tertiary amine used for conventional catalysis in the field, and can be one or more of triethylamine, diisopropylethylamine, DBU and piperidine, and the triethylamine is particularly preferred in the invention.
The amount of the tertiary amine is not limited in any way, and preferably the molar fraction is 5 to 10 percent of the compound B.
The dosage of the orthoesters compound is the conventional dosage for carrying out the condensation reaction in the field, and the molar ratio of the orthoesters compound to the compound B is particularly preferably 1.5: 1-3.0: 1, and further preferably 1.6: 1-1.8: 1.
The temperature of the condensation reaction is preferably 75-80 ℃.
The progress of the condensation reaction can be monitored by conventional monitoring means in the art such as Thin Layer Chromatography (TLC), Gas Chromatography (GC) or High Performance Liquid Chromatography (HPLC), and HPLC is particularly preferred in the present invention, and the end point of the reaction is further determined when the content of the compound B in the reaction system (HPLC%) < 0.5%.
In the present invention, the reaction time of the condensation reaction is preferably 3 to 15 hours, more preferably 4 to 5 hours.
The post-treatment method of the condensation reaction is a conventional post-treatment method in the field, and particularly preferably, the reaction solution is concentrated to obtain the crude compound C product so as to directly perform the next reaction, and further preferably, the reaction solution is cooled to 30-40 ℃ and then concentrated to obtain the crude compound C product so as to directly perform the next reaction.
The second technical scheme of the invention is as follows:
the invention further provides a preparation method of brinzolamide, which comprises the following steps: a) under the anhydrous condition, in an organic solvent and in the presence of tertiary amine, carrying out condensation reaction on the compound B and an orthoester compound at 70-80 ℃ to obtain a compound C; wherein the orthoesters compound is one or more of trimethyl orthoacetate, triethyl orthoacetate and trimethyl orthobenzoate; b) carrying out nucleophilic substitution reaction on the compound C and 4-tosyl chloride under the action of an acid-binding agent under an anhydrous condition to obtain a compound D; c) carrying out amination reaction on the compound D and an ethylamine water solution to obtain brinzolamide shown in the formula A;
wherein, the specific reaction conditions and parameters of the condensation reaction are as described in the first technical scheme; the specific reaction conditions and parameters for the nucleophilic substitution reaction and amination reaction are conventional in the art.
In the invention, preferably, after the reaction solution of the condensation reaction is cooled to 30-40 ℃, the reaction solution is concentrated to obtain the crude compound C, the reactions in the steps b) and C) are continued, and after the amination reaction is completed, the post-treatment mode comprises the following steps: acidifying the reaction system by using concentrated hydrochloric acid until the pH value is 1-5, and extracting by using an organic solvent; combining organic phases and extracting with dilute hydrochloric acid; and combining the extracted water phases, adding alkali to adjust the pH to 7-8, stirring, filtering the precipitate, and drying to obtain the brinzolamide shown in the formula A.
Before the post-treatment, preferably, firstly, the ethylamine in the reaction system of the amination reaction is steamed out, and the mixture is distilled and concentrated until the volume-to-mass ratio of the reaction system to the compound B is 7-8 mL/g, and then is cooled to-5-0 ℃;
the concentrated hydrochloric acid is preferably dripped at the temperature of 20-30 ℃;
the optimal end point of the acidification is that the pH value is 1-2;
after the acidification is finished, preferably, 0.1-0.4 mL/g of concentrated hydrochloric acid can be supplemented, and the mixture is stirred for 1-2 hours at the temperature of 20-30 ℃; the volume mass ratio of the concentrated hydrochloric acid to the compound B is 0.1-0.4 mL/g;
the organic solvent is methyl tert-butyl ether and/or ethyl acetate; the volume-mass ratio of the organic solvent to the compound B is preferably 5 mL/g; preferably, the organic solvent is used for extraction twice;
the concentration of the dilute hydrochloric acid is preferably 1-2N; the volume-mass ratio of the dilute hydrochloric acid to the compound B is preferably 2 mL/g;
the alkali adding mode is preferably as follows: adding sodium bicarbonate solid to adjust the pH value to 5-6; and adding water and a saturated sodium bicarbonate solution to adjust the pH value to 7-8. The volume-mass ratio of the water to the compound B is 3-6 mL/g, and the dosage of the sodium bicarbonate solid and the saturated sodium bicarbonate solution is based on the required pH.
After the filtration is finished, preferably further recovering and purifying the filtrate, wherein the recovered organic solvent is a mixed solvent of dichloromethane and methanol with a volume-to-mass ratio of 10:1(V/V) to the compound B of 4-8 mL/g, and more preferably 5-6 mL/g; the obtained crude product is recovered and further purified under the condition that ethyl acetate is used for thermal dissolution and recrystallization; wherein the volume-to-mass ratio of the ethyl acetate to the crude product is 2-5 mL/g, and preferably 2-3 mL/g.
In the second technical solution of the present invention, the step b) of the preparation method of brinzolamide preferably comprises the following steps: and under the anhydrous condition, under the action of an acid-binding agent, dripping the solution of the 4-tosyl chloride into the solution of the compound C to perform nucleophilic substitution reaction to obtain a compound D.
Wherein, in the solution of the compound C, the solvent is an organic solvent which is conventionally used in nucleophilic substitution reaction in the field, such as ethers or halogenated alkanes, and the like, and the invention particularly preferably selects one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and dichloromethane, and further preferably selects tetrahydrofuran.
In the solution of the compound C, the amount of the solvent is the amount of the solvent conventionally used in such reactions in the field, and the volume-to-mass ratio of the solvent to the compound C is particularly preferably 2-6 mL/g, and more preferably 4-5 mL/g.
Wherein, the acid-binding agent is a tertiary amine organic base which is conventionally used in the field and has stronger basicity than the C hydroxyl site of the compound, such as pyridine, triethylamine, diisopropylethylamine or DMAP, and the like, and triethylamine is preferred.
The dosage of the acid-binding agent is the conventional dosage in the field, and the molar ratio of the acid-binding agent to the compound C is preferably 1.0: 1-3.0: 1, and more preferably 2.5: 1-3.0: 1.
The acid-binding agent is added in a conventional manner in the field, such as direct addition or dropwise addition, and the temperature of the system is ensured to be-10-0 ℃, and the acid-binding agent is preferably dropwise added at a dropping speed of 1d/s at-10-0 ℃.
Wherein the reaction temperature of the nucleophilic substitution reaction is the conventional temperature condition of the nucleophilic substitution reaction in the field, and the reaction temperature is preferably-5 ℃, and further preferably-5-0 ℃.
Wherein, in the solution of 4-tosyl chloride, the solvent is an organic solvent which is conventionally used in nucleophilic substitution reaction in the field, such as ethers or halogenated alkanes, and the like, and the invention particularly preferably selects one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and dichloromethane, and further preferably selects tetrahydrofuran.
In the solution of 4-tosyl chloride, the amount of the solvent is the amount of the solvent conventionally used in the reaction in the field, and the volume-to-mass ratio of the solvent to the 4-tosyl chloride is preferably 1-3 mL/g, and more preferably 2 mL/g.
The dropping speed of the solution of the 4-tosyl chloride is the conventional dropping speed for carrying out the reaction in the field, and the invention particularly preferably selects 1-3 d/s, and further preferably selects 1-2 d/s.
Wherein, the reaction progress of the nucleophilic substitution reaction can be monitored by the conventional monitoring means in the field such as Thin Layer Chromatography (TLC), Gas Chromatography (GC) or High Performance Liquid Chromatography (HPLC), and the HPLC is particularly preferred in the present invention, and the end point of the reaction is further determined when the content (HPLC%) of the compound C in the reaction system is less than 0.5%.
In the second technical solution of the present invention, the step c) of the method for preparing brinzolamide preferably comprises the following steps: and (3) carrying out amination reaction on 70% of ethylamine water solution and the compound D at 10-20 ℃ to obtain brinzolamide shown in the formula A.
Wherein, in the 70% ethylamine aqueous solution, the 70% refers to the mass fraction of the ethylamine in the ethylamine aqueous solution.
Wherein the dropping condition of the 70% ethylamine water solution is preferably at a dropping speed of 1-5 d/s at-5-10 ℃, and more preferably at a dropping speed of 1-3 d/s at 0-5 ℃.
The dosage of the 70% ethylamine aqueous solution is the conventional dosage of amination reaction in the field, and the invention particularly preferably selects the molar ratio of the ethylamine to the compound D as 20: 1-40: 1, and further preferably 40: 1.
Wherein the reaction temperature of the amination reaction is further preferably 15-20 ℃.
Wherein, the reaction progress of the amination reaction can be monitored by the conventional monitoring means in the field such as Thin Layer Chromatography (TLC), Gas Chromatography (GC) or High Performance Liquid Chromatography (HPLC), and HPLC is particularly preferred in the present invention, and the end point of the reaction is further determined when the content (HPLC%) of the compound D in the reaction system is less than 0.5%.
Wherein, the post-treatment method of the amination reaction is a conventional post-treatment method in the field.
The third technical scheme of the invention is as follows:
the invention further provides a preparation method of brinzolamide, which comprises the following steps:
(1) under the anhydrous condition, under the action of an acid-binding agent, dripping the solution of 4-tosyl chloride into the solution of the compound C to carry out nucleophilic substitution reaction to prepare a compound D; (2) carrying out amination reaction on 70% of ethylamine water solution and the compound D at 10-20 ℃ to obtain brinzolamide shown in the formula A;
in the step (1), the solvent in the solution of the compound C is an organic solvent conventionally used in nucleophilic substitution in the art, such as ethers or halogenated alkanes, and the like, and in the present invention, one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and dichloromethane are particularly preferred, and tetrahydrofuran is further preferred.
In the step (1), the amount of the solvent in the solution of the compound C is the amount of the solvent conventionally used in such reactions in the field, and the volume-to-mass ratio of the solvent to the compound C is preferably 2 to 6mL/g, and more preferably 4 to 5 mL/g.
In the step (1), the acid-binding agent is a tertiary amine organic base which is conventionally used in the field and has stronger basicity than the C hydroxyl site of the compound, such as pyridine, triethylamine, diisopropylethylamine or DMAP, and the like, preferably triethylamine.
In the step (1), the dosage of the acid-binding agent is the conventional dosage in the field, and the molar ratio of the acid-binding agent to the compound C is particularly preferably 1.0: 1-3.0: 1, and further preferably 2.5: 1-3.0: 1.
In the step (1), the acid-binding agent is added in a conventional manner in the field, such as direct addition or dropwise addition, and the temperature of the system is ensured to be-10-0 ℃, and the acid-binding agent is preferably dropwise added at a dropping speed of 1d/s at-10-0 ℃.
In the step (1), the reaction temperature of the nucleophilic substitution reaction is the conventional temperature condition of the nucleophilic substitution reaction in the field, and the temperature is preferably-5 ℃, and more preferably-5-0 ℃.
In the step (1), in the solution of 4-tosyl chloride, the solvent is an organic solvent conventionally used in nucleophilic substitution in the art, such as ethers or halogenated alkanes, and the like, and in the present invention, one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and dichloromethane are particularly preferred, and tetrahydrofuran is further preferred.
In the step (1), in the solution of 4-tosyl chloride, the amount of the solvent is the amount of the solvent conventionally used in such reactions in the field, and the volume-to-mass ratio of the solvent to the 4-tosyl chloride is particularly preferably 1 to 3mL/g, and further preferably 2 mL/g.
In the step (1), the dropping speed of the solution of the 4-tosyl chloride is the conventional dropping speed for carrying out the reaction in the field, and the dropping speed is particularly preferably 1-3 d/s, and is further preferably 1-2 d/s.
In the step (1), the progress of the nucleophilic substitution reaction can be monitored by conventional monitoring means in the art such as Thin Layer Chromatography (TLC), Gas Chromatography (GC) or High Performance Liquid Chromatography (HPLC), and the like, and the HPLC is particularly preferred in the present invention, and the end point of the reaction is further determined when the content (HPLC%) of the compound C in the reaction system is less than 0.5%.
In the step (2), the 70% of the ethylamine in the 70% aqueous solution refers to the mass fraction of the ethylamine in the aqueous solution of the ethylamine.
In the step (2), the 70% ethylamine water solution is preferably added dropwise at a dropping speed of 1-5 d/s at-5-10 ℃, and more preferably at a dropping speed of 1-3 d/s at 0-5 ℃.
In the step (2), the amount of the 70% ethylamine aqueous solution is the conventional amount in the amination reaction in the field, and the invention particularly preferably selects the molar ratio of the ethylamine to the compound D as 20: 1-40: 1, and further preferably 40: 1.
In the step (2), the reaction temperature of the amination reaction is preferably 15-20 ℃.
In the step (2), the progress of the amination reaction can be monitored by conventional monitoring means in the art such as Thin Layer Chromatography (TLC), Gas Chromatography (GC) or High Performance Liquid Chromatography (HPLC), and the HPLC is particularly preferred in the present invention, and the end point of the reaction is further determined when the content (HPLC%) of the compound D in the reaction system is less than 0.5%.
In the step (2), the post-treatment method of the amination reaction is a conventional post-treatment method in the field.
In the third technical scheme of the present invention, the preparation method of brinzolamide preferably further comprises the following steps: under the anhydrous condition, in an organic solvent and in the presence of tertiary amine, carrying out a condensation reaction on a compound B and an orthoester compound at 70-80 ℃ to obtain a compound C, wherein the orthoester compound is one or more of trimethyl orthoacetate, triethyl orthoacetate and trimethyl orthobenzoate;
wherein, the specific reaction conditions and parameters of the condensation reaction are as described in the technical scheme I.
In the invention, preferably, after the reaction solution of the condensation reaction is cooled to 30-40 ℃, the reaction solution is concentrated to obtain the crude compound C, the reactions in the steps (2) and (3) are continued, and after the amination reaction is completed, the post-treatment mode comprises the following steps: acidifying the reaction system by using concentrated hydrochloric acid until the pH value is 1-5, and extracting by using an organic solvent; combining organic phases and extracting with dilute hydrochloric acid; and combining the extracted water phases, adding alkali to adjust the pH to 7-8, stirring, filtering the precipitate, and drying to obtain the brinzolamide shown in the formula A. Wherein, the post-treatment mode is preferably as described in the second technical proposal.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
In the invention, when more than two steps of reactions are combined in the synthetic route of the brinzolamide, the reaction intermediate is not subjected to post-treatment, but directly takes crude products to participate in the next step of reaction, and the yield is calculated by taking the theoretical yield of the reaction in the previous step as 100%.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
according to the invention, tertiary amine is used as a catalyst in the synthesis of the intermediate C, so that the reaction time is shortened, the dosage of a protective reagent is reduced, the product yield and purity are improved, and the reaction temperature is reduced;
in the preferred scheme of the invention, 4-tosyl chloride tetrahydrofuran solution is dropped instead of directly adding 4-tosyl chloride, so that the generation of hydrogen chloride acid mist can be effectively avoided, and the industrial operation is easy;
in the preferred scheme of the invention, the amination reaction is completely carried out and then the concentration is carried out, so that the post-treatment volume is reduced, and the large-scale production is facilitated;
fourthly, the amount of hydrochloric acid required to be added is accurately judged by adjusting the pH value in the optimized post-treatment step, so that the using amount of concentrated hydrochloric acid is greatly reduced;
fifthly, in the preferable post-treatment step, the pH is adjusted by mixing and adding the solid sodium bicarbonate and the sodium bicarbonate solution, so that excessive use of the solid sodium bicarbonate is avoided, and the burning residues are effectively controlled;
sixthly, the product prepared by the preparation method has the yield of 60.2 percent of the product separated out for the first time, and the total yield is 65.3 percent after the mother solution is recovered, which is superior to the reaction result in the prior art; the HPLC purity of the product is as high as 98.1 percent, and the chiral HPLC purity of the product is as high as 99.9 percent; and the operation is simple, and the cost is saved.
Drawings
FIG. 1 is a HPLC monitoring spectrum of the progress of the condensation reaction in example 9.
FIG. 2 is a HPLC monitoring spectrum of the progress of the condensation reaction in comparative example 2.
FIG. 3 is a HPLC purity check chart of the amination reaction product in comparative example 2.
FIG. 4 is a HPLC purity check chart of the product recovered by the amination reaction in comparative example 2.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Unless otherwise specified, in the following examples:
the reaction progress of the condensation reaction (synthesis of compound C) was monitored by HPLC, with specific HPLC monitoring conditions: a chromatographic column: acclaim c184.6mm × 250mm,5 μm; mobile phase: mobile phase A: buffer/acetonitrile 70/30; mobile phase B: buffer/acetonitrile 60/40; buffer solution: 5.0mL of triethylamine to 1000mL of water, and adjusting the pH value to 4.0 by phosphoric acid; flow rate: 1.0 mL/min; column temperature: 30 ℃; detection wavelength: 250 nm; sample introduction volume: 10 mu L of the solution; product peak retention time of compound C: R.T ═ 7.3 min; retention time of unreacted starting material peak compound B: R.T is 6.8 min.
The reaction progress of the amination reaction (synthesis of the product brinzolamide A) is monitored by HPLC, and the specific HPLC monitoring conditions are as follows: a chromatographic column: acclaim c184.6mm × 250mm,5 μm; mobile phase: mobile phase A: buffer/acetonitrile 70/30; mobile phase B: buffer/acetonitrile 60/40; buffer solution: 5.0mL of triethylamine to 1000mL of water, and adjusting the pH value to 4.0 by phosphoric acid; flow rate: 1.0 mL/min; column temperature: 30 ℃; detection wavelength: 250 nm; sample introduction volume: 10 mu L of the solution; retention time of product peak: R.T is 4.2 min; retention time of peaks of unreacted raw materials: R.T min 5.4 min.
The HPLC purity determination conditions of the product brinzolamide A are the same as above.
The chiral HPLC purity determination conditions of the product brinzolamide A are as follows: chiracel AD-H column,254nm,30 ℃, Ethanol-Hexane-Methanol (50:40:10), flow ═ 0.7mL/min, tR＝15.1min(major)and18.1min.
Method for measuring residue on ignition: the porcelain crucible after burning for 30 minutes at 600 ℃. + -. 50 ℃ and cooling in a desiccator was accurately weighed (m)1) (ii) a Adding 1.0g of sample, and accurately weighing (m)2) The sample was wetted with 1mL of sulfuric acid, then slowly heated at as low a temperature as possible until the sample was completely carbonized, and cooled. The residue was wetted with 1mL of sulfuric acid and slowly heated until no white smoke was formed. Glowing at 600 ℃. + -. 50 ℃ until thorough ashing. Cooled in a desiccator, and accurately weighed (m)3) And calculating the residue percentage. If the residue content exceeds the limit, the mixture is continuously moistened with sulfuric acid, heated, ignited for 30min, and precisely weighed (m)n) Until the difference between the weights of the residues on ignition is not more than 0.5 mg.
ωResidue on ignition＝(m2-m3)/(m2-m1)×100％
In the formula: m is1The mass of the porcelain crucible is expressed in g; m is2The mass of the porcelain crucible containing the sample before ignition is expressed in g; m is3The mass of the porcelain crucible containing the residue after glowing constant weight is expressed in g.
Preparation of reaction raw materials: the compound B (S) -4-hydroxy-2- (3-methoxypropyl) -3, 4-dihydro-thieno [3,2-e ] -1, 2-thiazine-6-sulfonamide-1, 1-dioxide is prepared by reference to the following synthetic route (ref: organic Process Research and Development,1999,3(2), 114-.
Compound B nuclear magnetic data:1H NMR(300MHz,DMSO)δ8.04(s,2H),7.60(s,1H),6.15(d,J＝6.0Hz,1H),4.83(d,J＝5.2Hz,1H),3.92(dd,J＝15.3,4.6Hz,1H),3.74(dd,J＝15.3,5.6Hz,1H),3.34(dt,J＝9.3,6.6Hz,4H),3.23(s,3H),1.83(t,J＝6.5Hz,2H).
example 1:
compound B (10.0g, 28.1mmol) was added to 90mL acetonitrile, trimethyl orthoacetate (5.4g, 44.9mmol) and triethylamine (0.28g, 2.8mmol) were added with stirring, and after addition, the temperature was raised to 78 deg.C and the reaction was stirred for 4h, which was monitored by HPLC to show completion. Cooling to 40 ℃, distilling under reduced pressure, and concentrating to the minimum volume to obtain a crude product of the compound C.
Dissolving the crude compound C in 30mL of tetrahydrofuran, cooling to-10 ℃, and slowly dropwise adding triethylamine (6.2g, 61.7mmol) at the dropping speed of 1 d/s; after the addition, a solution of 4-toluenesulfonyl chloride (10.7g, 61.7mmol) in 20mL of tetrahydrofuran was added dropwise at a dropping rate of 1 d/s. After the addition, the reaction was stirred at 5 ℃ for about 3 hours to complete the reaction.
70% aqueous ethylamine (72.2g, 1.12M) was slowly added dropwise at a rate of 3d/s at a controlled temperature of 10 ℃. After the addition, the temperature is controlled to be 20 ℃ and the stirring is carried out, and the reaction is completed within about 15 hours. Concentrating to 70-80 mL by reduced pressure distillation, and cooling to 0 ℃.
Controlling the temperature below 30 ℃, dropwise adding concentrated hydrochloric acid (12mol/L) to adjust the pH value to 1-2, then supplementing about 3mL of concentrated hydrochloric acid (12mol/L), and stirring at room temperature for 1 h.
The reaction was extracted twice with methyl tert-butyl ether (2 x 50 mL). The organic phases were combined and extracted once with dilute hydrochloric acid (1mol/L, 20 mL). And (3) combining the water phases, slowly adding sodium bicarbonate solid, adjusting the pH value to 5-6, adding 30mL of water, adjusting the pH value to 7-8 by using 7% sodium bicarbonate solution, stirring at room temperature for 15h after the adjustment is finished, and slowly crystallizing.
Filtering, leaching a filter cake by using 10mL of water, and drying the filter cake to obtain 6.5g of a product with the purity of 98.1 percent, the yield of 60.2 percent, the ignition residue of 0.1 percent and the chiral purity of 99.9 percent.
Nuclear magnetic data of the product:1H NMR(300MHz,DMSO)δ8.04(bs,2H),7.71(s,1H),4.15(t,J＝7.0Hz,1H),3.84(m,2H),4.12(t,J＝7.0Hz,1H),3.86(m,2H),3.5(m,1H),3.38(t,J＝7.0Hz,2H),3.25(s,3H),3.15(m,1H),2.62(m,2H),2.50(bs,1H),1.85(m,2H),1.08(t,J＝7.0Hz,3H).
example 2:
compound B (10.0g, 28.1mmol) was added to 90mL acetonitrile and trimethyl orthoacetate (6.1g, 50.5mmol) and triethylamine (0.28g, 2.8mmol) were added with stirring, after which the temperature was raised to 71 deg.C and stirred for 3h, which was monitored by HPLC to show completion of the reaction. Cooling to 32 ℃, distilling under reduced pressure, and concentrating to the minimum volume to obtain a crude product of the compound C.
Dissolving the crude compound C in 30mL of tetrahydrofuran, cooling to 0 ℃, and slowly dropwise adding triethylamine (6.2g, 61.7mmol) at the dropping speed of 1 d/s; after the addition, a solution of 4-toluenesulfonyl chloride (10.7g, 61.7mmol) in 20mL of tetrahydrofuran was added dropwise at a dropping rate of 1 d/s. After the addition, the temperature is controlled to be-5 ℃ and the mixture is stirred, and the reaction is completed within about 3 hours.
70% aqueous ethylamine (72.2g, 1.12M) was slowly added dropwise at a rate of 1d/s at a controlled temperature of 5 ℃. After the addition, the temperature is controlled at 10 ℃ and the mixture is stirred, and the reaction is completed within about 15 hours. Concentrating to 70-80 mL by reduced pressure distillation, and cooling to 0 ℃.
Controlling the temperature below 30 ℃, dropwise adding concentrated hydrochloric acid (12mol/L) to adjust the pH value to 1-2, then supplementing about 3mL of concentrated hydrochloric acid (12mol/L), and stirring at room temperature for 1 h.
The reaction was extracted twice with methyl tert-butyl ether (2 x 50 mL). The organic phases were combined and extracted once with dilute hydrochloric acid (1mol/L, 20 mL). And (3) combining the water phases, slowly adding sodium bicarbonate solid, adjusting the pH value to 5-6, adding 30mL of water, adjusting the pH value to 7-8 by using 7% sodium bicarbonate solution, stirring at room temperature for 15h after the adjustment is finished, and slowly crystallizing.
Filtering, leaching a filter cake by using 10mL of water, and drying the filter cake to obtain 6.4g of a product with the purity of 97.8 percent, the yield of 59.5 percent, the ignition residue of 0.1 percent and the chiral purity of 99.9 percent.
Example 3:
compound B (10.0g, 28.1mmol) was added to 90mL acetonitrile and trimethyl orthoacetate (5.4g, 44.9mmol) and diisopropylethylamine (0.18g, 1.4mmol) were added with stirring, after which the temperature was raised to 78 deg.C and stirring was continued for 4h, as monitored by HPLC showing complete reaction. Cooling to 40 ℃, distilling under reduced pressure, and concentrating to the minimum volume to obtain a crude product of the compound C.
The crude compound C was dissolved in 30mL of tetrahydrofuran, cooled to-10 deg.C, triethylamine (6.2g, 61.7mmol) was slowly added dropwise at a rate of 1d/s, and after addition, a solution of 4-tosyl chloride (10.7g, 61.7mmol) in 20mL of tetrahydrofuran was added dropwise at a rate of 2 d/s. After the addition, the temperature is controlled to be-4 ℃ and the stirring is carried out, and the reaction is completed within about 3 hours.
70% aqueous ethylamine (72.2g, 1.12M) was slowly added dropwise at a rate of 3d/s at a controlled temperature of 10 ℃. After the addition, the temperature is controlled at 12 ℃ and the stirring is carried out, and the reaction is completed within about 15 hours. Concentrating to 70-80 mL by reduced pressure distillation, and cooling to 0 ℃.
Controlling the temperature below 30 ℃, dropwise adding concentrated hydrochloric acid (12mol/L) to adjust the pH value to 1-2, then supplementing about 3mL of concentrated hydrochloric acid (12mol/L), and stirring at room temperature for 1 h.
The reaction was extracted twice with methyl tert-butyl ether (2 x 50 mL). The organic phases were combined and extracted once with dilute hydrochloric acid (1mol/L, 20 mL). And (3) combining the water phases, slowly adding sodium bicarbonate solid, adjusting the pH value to 5-6, adding 30mL of water, adjusting the pH value to 7-8 by using 7% sodium bicarbonate solution, stirring at room temperature for 15h after the adjustment is finished, and slowly crystallizing.
Filtering, leaching a filter cake by using 10mL of water, and drying the filter cake to obtain 6.3g of a product with the purity of 98.1 percent, the yield of 58.6 percent, 0.2 percent of ignition residue and the chiral purity of 99.6 percent.
Example 4
Compound B (10.0g, 28.1mmol) was added to 150mL dioxane, triethyl orthoacetate (7.3g, 44.9mmol) and DBU (0.43g, 2.8mmol) were added with stirring, and after addition, the temperature was raised to 70 ℃ and stirred for 4h, which was monitored by HPLC to show completion of the reaction. Cooling to 30 ℃, distilling under reduced pressure, and concentrating to the minimum volume to obtain a crude product of the compound C.
The crude compound C was dissolved in 30mL of dimethyltetrahydrofuran, cooled to-10 deg.C, and triethylamine (8.5g, 84.3mmol) was slowly added dropwise at a rate of 1d/s, after which a solution of 4-tosyl chloride (10.7g, 61.7mmol) in 20mL of dimethyltetrahydrofuran was added dropwise at a rate of 3 d/s. After the addition, the reaction was completed in about 3 hours with stirring at 0 ℃.
70% aqueous ethylamine (72.2g, 1.12M) was slowly added dropwise at a rate of 5d/s at a controlled temperature of 0 ℃. After the addition, the temperature is controlled to be 20 ℃ and the stirring is carried out, and the reaction is completed within about 15 hours. Concentrating to 70-80 mL by reduced pressure distillation, and cooling to 0 ℃.
Controlling the temperature below 30 ℃, dropwise adding concentrated hydrochloric acid (12mol/L) to adjust the pH value to 1-2, then supplementing about 4mL of concentrated hydrochloric acid (12mol/L), and stirring at room temperature for 1 h.
The reaction was extracted twice with methyl tert-butyl ether (2 x 50 mL). The organic phases were combined and extracted once with dilute hydrochloric acid (1mol/L, 20 mL). And (3) combining the water phases, slowly adding sodium bicarbonate solid, adjusting the pH value to 5-6, adding 40mL of water, adjusting the pH value to 7-8 by using 7% sodium bicarbonate solution, stirring at room temperature for 15h after the adjustment is finished, and slowly crystallizing.
Filtering, leaching a filter cake by using 10mL of water, and drying the filter cake to obtain 6.4g of a product with the purity of 98.1 percent, the yield of 59.5 percent, the ignition residue of 0.1 percent and the chiral purity of 99.7 percent.
Example 5
Compound B (10.0g, 28.1mmol) was added to 100mL DMF and trimethyl orthobenzoate (8.5g, 44.9mmol) and triethylamine (0.28g, 2.8mmol) were added with stirring and after addition, the temperature was raised to 75 deg.C and stirred for 4h, as monitored by HPLC showing complete reaction. Cooling to 40 ℃, distilling under reduced pressure, and concentrating to the minimum volume to obtain a crude product of the compound C.
The crude compound C was dissolved in 30mL dioxane, cooled to-10 deg.C, pyridine (5.6g, 70.3mmol) was slowly added dropwise at a rate of 1d/s, and after addition was complete, a solution of 4-tosyl chloride (10.7g, 61.7mmol) in 20mL dioxane was added dropwise at a rate of 2 d/s. After the addition, the reaction was stirred at 5 ℃ for about 3 hours to complete the reaction.
70% aqueous ethylamine (72.2g, 1.12M) was slowly added dropwise at a rate of 5d/s at a controlled temperature of-5 ℃. After the addition, the temperature is controlled to be 20 ℃ and the stirring is carried out, and the reaction is completed within about 15 hours. Concentrating to 70-80 mL by reduced pressure distillation, and cooling to 0 ℃.
Controlling the temperature below 30 ℃, dropwise adding concentrated hydrochloric acid (12mol/L) to adjust the pH value to 1-2, then supplementing about 1mL of concentrated hydrochloric acid (12mol/L), and stirring at room temperature for 1 h.
The reaction was extracted twice with methyl tert-butyl ether (2 x 50 mL). The organic phases were combined and extracted once with dilute hydrochloric acid (1mol/L, 20 mL). And (3) combining the water phases, slowly adding sodium bicarbonate solid, adjusting the pH value to 5-6, adding 60mL of water, adjusting the pH value to 7-8 by using 7% sodium bicarbonate solution, stirring at room temperature for 15h after the adjustment is finished, and slowly crystallizing.
Filtering, leaching a filter cake by using 10mL of water, and drying the filter cake to obtain 6.3g of a product with the purity of 98.1 percent, the yield of 58.6 percent, the ignition residue of 0.1 percent and the chiral purity of 99.7 percent.
Example 6
Compound B (10.0g, 28.1mmol) was added to 50mL acetonitrile and trimethyl orthoacetate (4.4g, 36.5mmol) and piperidine (0.24g, 2.8mmol) were added with stirring, after which the temperature was raised to 80 deg.C and stirred for 4h, which was monitored by HPLC to show completion of the reaction. Cooling to 40 ℃, distilling under reduced pressure, and concentrating to the minimum volume to obtain a crude product of the compound C.
The crude compound C was dissolved in 30mL tetrahydrofuran, cooled to-10 deg.C and diisopropylethylamine (8.0g, 61.7mmol) was added slowly dropwise at 1d/s, after which a solution of 4-toluenesulfonyl chloride (10.7g, 61.7mmol) in 20mL tetrahydrofuran was added dropwise at 3 d/s. After the addition, the reaction was completed in about 3 hours with stirring at 0 ℃.
70% aqueous ethylamine (72.2g, 1.12M) was slowly added dropwise at a rate of 3d/s at a controlled temperature of 10 ℃. After the addition, the temperature is controlled to be 20 ℃ and the stirring is carried out, and the reaction is completed within about 15 hours. Concentrating to 70-80 mL by reduced pressure distillation, and cooling to 0 ℃.
Controlling the temperature below 30 ℃, dropwise adding concentrated hydrochloric acid (12mol/L) to adjust the pH value to 1-2, then supplementing about 3mL of concentrated hydrochloric acid (12mol/L), and stirring at room temperature for 1 h.
The reaction was extracted twice with methyl tert-butyl ether (2 x 50 mL). The organic phases were combined and extracted once with dilute hydrochloric acid (1mol/L, 20 mL). And (3) combining the water phases, slowly adding sodium bicarbonate solid, adjusting the pH value to 5-6, adding 40mL of water, adjusting the pH value to 7-8 by using 7% sodium bicarbonate solution, stirring at room temperature for 15h after the adjustment is finished, and slowly crystallizing.
Filtering, leaching the filter cake with 10mL of water, and drying the filter cake to obtain 6.1g of a product with the purity of 98.1 percent, the yield of 56.7 percent, the ignition residue of 0.1 percent and the chiral purity of 99.8 percent.
Example 7
Compound B (10.0g, 28.1mmol) was added to 80mL acetonitrile and trimethyl orthoacetate (5.1g, 42.2mmol) and triethylamine (0.28g, 2.8mmol) were added with stirring, after which the temperature was raised to 75 deg.C and stirred for 4h, as monitored by HPLC, indicating completion of the reaction. Cooling to 40 ℃, distilling under reduced pressure, and concentrating to the minimum volume to obtain a crude product of the compound C.
The crude compound C was dissolved in 30mL of dichloromethane, cooled to-10 deg.C, DMAP (7.5g, 61.7mmol) was added slowly in portions, and after addition, a solution of 4-toluenesulfonyl chloride (10.7g, 61.7mmol) in 20mL of dichloromethane was added dropwise at a rate of 3 d/s. After the addition, the reaction was stirred at 5 ℃ for about 3 hours to complete the reaction.
At a controlled temperature of 0 deg.C, 70% aqueous ethylamine (72.2g, 1.12M) was slowly added dropwise at a rate of 3 d/s. After the addition, the temperature is controlled at 15 ℃ and the mixture is stirred, and the reaction is completed within about 15 hours. Concentrating to 70-80 mL by reduced pressure distillation, and cooling to 0 ℃.
Controlling the temperature below 30 ℃, dropwise adding concentrated hydrochloric acid (12mol/L) to adjust the pH value to 1-2, then supplementing about 3mL of concentrated hydrochloric acid (12mol/L), and stirring at room temperature for 1 h.
The reaction was extracted twice with methyl tert-butyl ether (2 x 50 mL). The organic phases were combined and extracted once with dilute hydrochloric acid (1mol/L, 20 mL). And (3) combining the water phases, slowly adding sodium bicarbonate solid, adjusting the pH value to 5-6, adding 40mL of water, adjusting the pH value to 7-8 by using 7% sodium bicarbonate solution, stirring at room temperature for 15h after the adjustment is finished, and slowly crystallizing.
Filtering, leaching a filter cake by using 10mL of water, and drying the filter cake to obtain 6.6g of a product with the purity of 98.1 percent, the yield of 61.4 percent, the ignition residue of 0.2 percent and the chiral purity of 99.7 percent.
Example 8
Compound B (10.0g, 28.1mmol) was added to 90mL acetonitrile and trimethyl orthoacetate (5.4g, 44.9mmol) and triethylamine (0.28g, 2.8mmol) were added with stirring, after which the temperature was raised to 78 deg.C and stirred for 4h, as monitored by HPLC, indicating completion of the reaction. Cooling to 40 ℃, distilling under reduced pressure, and concentrating to the minimum volume to obtain a crude product of the compound C.
The crude compound C was dissolved in 30mL of tetrahydrofuran, cooled to-10 deg.C, triethylamine (6.2g, 61.7mmol) was slowly added dropwise at a rate of 1d/s, and after addition, a solution of 4-tosyl chloride (10.7g, 61.7mmol) in 20mL of tetrahydrofuran was added dropwise at a rate of 1 d/s. After the addition, the reaction was stirred at 5 ℃ for about 3 hours to complete the reaction.
70% aqueous ethylamine (72.2g, 1.12M) was slowly added dropwise at a rate of 2d/s at a controlled temperature of 5 ℃. After the addition, the temperature is controlled to be 20 ℃ and the stirring is carried out, and the reaction is completed within about 15 hours. Concentrating to 70-80 mL by reduced pressure distillation, and cooling to 0 ℃.
Controlling the temperature below 30 ℃, dropwise adding concentrated hydrochloric acid (12mol/L) to adjust the pH value to 1-2, then supplementing about 3mL of concentrated hydrochloric acid (12mol/L), and stirring at room temperature for 1 h.
The reaction was extracted twice with methyl tert-butyl ether (2 x 50 mL). The organic phases were combined and extracted once with dilute hydrochloric acid (1mol/L, 20 mL). And (3) combining the water phases, slowly adding sodium bicarbonate solid, adjusting the pH value to 5-6, adding 30mL of water, adjusting the pH value to 7-8 by using 7% sodium bicarbonate solution, stirring at room temperature for 15h after the adjustment is finished, and slowly crystallizing.
Filtering, leaching a filter cake by using 10mL of water, and drying the filter cake to obtain 6.4g of a product with the purity of 98.1 percent, the yield of 59.5 percent, the ignition residue of 0.1 percent and the chiral purity of 99.9 percent.
Example 9:
compound B (50.0g, 140.7mmol) was added to 450mL acetonitrile, trimethyl orthoacetate (27.0g, 225.1mmol) and triethylamine (1.4g, 14.0mmol) were added with stirring, and after addition, the temperature was raised to 78 deg.C and the mixture was stirred for 5h, HPLC monitoring showed completion, and the results of HPLC monitoring are shown in Table 1 (see FIG. 1). Cooling to 40 ℃, distilling under reduced pressure, and concentrating to the minimum volume to obtain a crude product of the compound C.
The crude compound C was dissolved in 180mL of tetrahydrofuran, cooled to-10 deg.C and triethylamine (31.3g, 309.5mmol) was slowly added dropwise at a rate of 1d/s, after which 4-toluenesulfonyl chloride (53.5g, 280.6mmol) in 70mL of tetrahydrofuran was added dropwise at a rate of 3 d/s. After the addition, the temperature is controlled to be-4 ℃ and the reaction is completed in about 3 hours.
70% aqueous ethylamine (361.0g, 5.6M) was slowly added dropwise at a rate of 5d/s while controlling the temperature to 10 ℃ or lower. After the addition, the temperature is controlled at 12 ℃ and the stirring is carried out, and the reaction is completed within about 15 hours. Concentrating to 70-80 mL by reduced pressure distillation, and cooling to 0 ℃.
Controlling the temperature below 30 ℃, dropwise adding concentrated hydrochloric acid (12mol/L) to adjust the pH value to 1-2, then supplementing about 14mL of concentrated hydrochloric acid (12mol/L), and stirring at room temperature for 1 h.
The reaction was extracted twice with methyl tert-butyl ether (2 x 250 mL). The organic phases were combined and extracted once with dilute hydrochloric acid (1mol/L, 100 mL). And (3) combining the water phases, slowly adding sodium bicarbonate solid, adjusting the pH value to 5-6, adding 150mL of water, adjusting the pH value to 7-8 by using 7% sodium bicarbonate solution, stirring at room temperature for 15h after the adjustment is finished, and slowly crystallizing.
Filtering, leaching filter cakes by using 30mL of water, and drying the filter cakes to obtain 35.4g of products with the purity of 98.3%.
To the filtered mother liquor was added 250mL of dichloromethane and 25mL of methanol, followed by stirring, extraction, liquid separation, and concentration of the organic phase to dryness to give 4.6g of a yellow viscous substance, and 10mL of ethyl acetate was added. Heating to 70-75 ℃ for dissolving, slowly cooling to 0-10 ℃, stirring for 1-2 h, separating out white solid, continuously stirring for 3-4 h, filtering, leaching filter cakes with 3mL of water, and drying the filter cakes to obtain 2.4g of a product with the purity of 97.3%.
The mixture is mixed, the purity is 98.1 percent, the total yield is 65.3 percent, the ignition residue is 0.08 percent, and the chiral purity is 99.7 percent.
TABLE 1
Example 10:
compound B (10.0g, 28.1mmol) was added to 90mL acetonitrile and trimethyl orthoacetate (5.4g, 44.9mmol) and triethylamine (0.28g, 2.8mmol) were added with stirring, after which the temperature was raised to 78 deg.C and stirred for 4h, as monitored by HPLC, indicating completion of the reaction. Cooling to 40 ℃, distilling under reduced pressure, and concentrating to the minimum volume to obtain a crude product of the compound C.
The crude compound C was dissolved in 30mL of tetrahydrofuran, cooled to-10 deg.C, triethylamine (6.2g, 61.7mmol) was slowly added dropwise at a rate of 1d/s, and after addition, a solution of 4-tosyl chloride (10.7g, 61.7mmol) in 20mL of tetrahydrofuran was added dropwise at a rate of 1 d/s. After the addition, the temperature is controlled to be 5 ℃, and the reaction is completed in about 3 hours.
70% aqueous ethylamine (72.2g, 1.12M) was slowly added dropwise at a rate of 3d/s while controlling the temperature to 10 ℃ or lower. After the addition, the temperature is controlled to be 20 ℃ and the stirring is carried out, and the reaction is completed within about 15 hours. Concentrating to 70-80 mL by reduced pressure distillation, supplementing 40mL of tetrahydrofuran, and cooling to 0 ℃.
Controlling the temperature below 30 ℃, dropwise adding concentrated hydrochloric acid (12mol/L) to adjust the pH value to 1-2, then supplementing about 3mL of concentrated hydrochloric acid (12mol/L), and stirring at room temperature for 1 h.
The reaction was extracted twice with methyl tert-butyl ether (2 x 50 mL). The organic phases were combined and extracted once with dilute hydrochloric acid (1mol/L, 20 mL). And (3) combining the water phases, slowly adding sodium bicarbonate solid, adjusting the pH value to 7-8, stirring at room temperature for 15h after the adjustment is finished, and slowly crystallizing.
Filtering, leaching filter cakes by using 10mL of water, and drying the filter cakes to obtain 6.6g of a product with the purity of 97.6 percent and the yield of 61.3 percent. 3.1% of ignition residue and 99.7% of chiral purity.
Example 11:
compound B (10.0g, 28.1mmol) was added to 90mL acetonitrile and trimethyl orthoacetate (5.4g, 44.9mmol) and triethylamine (0.28g, 2.8mmol) were added with stirring, after which the temperature was raised to 78 deg.C and stirred for 4h, as monitored by HPLC, indicating completion of the reaction. Cooling to 40 ℃, distilling under reduced pressure, and concentrating to the minimum volume to obtain a crude product of the compound C.
The crude compound C was dissolved in 30mL of tetrahydrofuran, cooled to-10 deg.C, triethylamine (6.2g, 61.7mmol) was slowly added dropwise at a rate of 1d/s, and after addition, a solution of 4-tosyl chloride (10.7g, 61.7mmol) in 20mL of tetrahydrofuran was added dropwise at a rate of 1 d/s. After the addition, the temperature is controlled to be 5 ℃, and the reaction is completed in about 3 hours.
70% aqueous ethylamine (72.2g, 1.12M) was slowly added dropwise at a rate of 3d/s while controlling the temperature to 10 ℃ or lower. After the addition, the temperature was controlled to 25 ℃ and the mixture was stirred for 15 hours, and TLC showed that the starting material remained. Concentrating to 70-80 mL by reduced pressure distillation, supplementing 40mL of tetrahydrofuran, and cooling to 0 ℃.
Controlling the temperature below 30 ℃, dropwise adding concentrated hydrochloric acid (12mol/L) to adjust the pH value to 1-2, then supplementing about 3mL of concentrated hydrochloric acid (12mol/L), and stirring at room temperature for 1 h.
The reaction was extracted twice with methyl tert-butyl ether (2 x 50 mL). The organic phases were combined and extracted once with dilute hydrochloric acid (1mol/L, 20 mL). And (3) combining the water phases, slowly adding sodium bicarbonate solid, adjusting the pH value to 5-6, adding 30mL of water, adjusting the pH value to 7-8 by using 7% sodium bicarbonate solution, stirring at room temperature for 15h after the adjustment is finished, and slowly crystallizing.
Filtering, leaching filter cakes by using 10mL of water, and drying the filter cakes to obtain 5.1g of a product with the purity of 98.0 percent and the yield of 47.4 percent. 0.2% of ignition residue and 99.8% of chiral purity.
Comparative example 1:
compound B (10.0g, 28.1mmol) was added to 90mL acetonitrile and trimethyl orthoacetate (5.4g, 44.9mmol) was added with stirring, after which the temperature was raised to 78 deg.C and stirred for 15h, which was monitored by HPLC to show completion of the reaction. Cooling to 40 ℃, distilling under reduced pressure, and concentrating to the minimum volume to obtain a crude product of the compound C.
The crude compound C was dissolved in 30mL of tetrahydrofuran, cooled to-10 deg.C, triethylamine (6.2g, 61.7mmol) was slowly added dropwise at a rate of 1d/s, and after addition, a solution of 4-tosyl chloride (10.7g, 61.7mmol) in 20mL of tetrahydrofuran was added dropwise at a rate of 1 d/s. After the addition, the temperature is controlled at 0 ℃ for about 3 hours to complete the reaction.
70% aqueous ethylamine (72.2g, 1.12M) was slowly added dropwise at a rate of 3d/s while controlling the temperature to 10 ℃ or lower. After the addition, the temperature is controlled to be 20 ℃ and the stirring is carried out, and the reaction is completed within about 15 hours. Concentrating to 70-80 mL by reduced pressure distillation, and cooling to 0 ℃.
Controlling the temperature below 30 ℃, dropwise adding concentrated hydrochloric acid (12mol/L) to adjust the pH value to 1-2, then supplementing about 3mL of concentrated hydrochloric acid (12mol/L), and stirring at room temperature for 1 h.
The reaction was extracted twice with methyl tert-butyl ether (2 x 50 mL). The organic phases were combined and extracted once with dilute hydrochloric acid (1mol/L, 20 mL). And (3) combining the water phases, slowly adding sodium bicarbonate solid, adjusting the pH value to 5-6, adding 30mL of water, adjusting the pH value to 7-8 by using 7% sodium bicarbonate solution, stirring at room temperature for 15h after the adjustment is finished, and slowly crystallizing.
Filtering, leaching the filter cake with 10mL of water, and drying the filter cake to obtain 5.5g of a product with the purity of 97.0 percent, the yield of 51.1 percent, the ignition residue of 0.1 percent and the chiral purity of 99.5 percent.
Comparative example 2: (experiments were carried out according to the preparation method reported by Conrow. R.E. et al in Organic Process Research & Development1999,3, 114-120.)
Compound B (50.0g, 140.7mmol) was added to 456mL acetonitrile, N2Trimethyl orthoacetate (38.9g, 323.5mmol) was added with stirring, and after addition, the temperature was raised to reflux (external 85 ℃ C.) and stirred for 15h, and the HPLC monitoring results are shown in Table 2 (see FIG. 2). Cooling to 30 ℃, distilling under reduced pressure, and concentrating to the minimum volume to obtain a crude product of the compound C.
Dissolve the crude Compound C in 250mL of tetrahydroFuran, N2Protecting and cooling to-10 ℃. Triethylamine (31.5g, 309.5mmol) was slowly added dropwise, and after addition was complete, 4-toluenesulfonyl chloride (53.6g, 280.6mmol) was added portionwise with exotherm. After the addition, the temperature is controlled to be about-2 ℃, and the reaction is completed within about 2 hours.
Controlling the temperature below 10 ℃, slowly dropwise adding 70% ethylamine water solution (271.0g, 4.2M), controlling the temperature at 12 ℃ and stirring after the addition is finished, and completely reacting for about 15 hours.
Cooling to-5 ℃, dropwise adding about 340mL of concentrated hydrochloric acid (12mol/L), releasing heat, slowly dropwise adding at the temperature controlled below 50 ℃, and finishing dropwise adding within about 30 minutes. Cooling to 25 deg.C, and stirring for 2 h.
The reaction was extracted twice with methyl tert-butyl ether (2 x 200 mL). The organic phases were combined and extracted once with dilute hydrochloric acid (1mol/L, 22 mL). Mixing the water phases, slowly adding sodium bicarbonate solid, adjusting pH to 8, stirring at room temperature of 20 deg.C for 15 hr, and slowly crystallizing.
Filtering, leaching filter cakes by using 30mL of water, and drying the filter cakes to obtain 25.2g of products with the purity of 96.7%. The HPLC test results are shown in Table 3 (see FIG. 3).
Extracting the filtrate twice by using ethyl acetate (2 x 450mL), separating the liquid, adding anhydrous magnesium sulfate into the organic phase, drying, filtering, concentrating the organic phase until the organic phase is dried to obtain 7.5g of yellow solid, recrystallizing by using 22mL of isopropanol, slowly reducing the temperature to 0-10 ℃, stirring for 1-2 h, separating out white solid, continuously stirring for 3-4 h, filtering, leaching the filter cake by using 3mL of water, and drying the filter cake to obtain 4.6g of a product with the HPLC purity of 94.7%. The HPLC test results are shown in Table 4 (see FIG. 4).
The product total yield is 55.4 percent, the purity is 96.3 percent, the ignition residue is 0.5 percent, and the chiral purity is 99.5 percent.
TABLE 2
TABLE 3
TABLE 4
Claims (12)
1. A preparation method of a brinzolamide intermediate shown as a compound C comprises the following steps: under the anhydrous condition, in an organic solvent and in the presence of tertiary amine, carrying out condensation reaction on the compound B and an orthoester compound at 70-80 ℃; wherein the orthoesters compound is one or more of trimethyl orthoacetate, triethyl orthoacetate and trimethyl orthobenzoate;
the molar ratio of the orthoesters compound to the compound B is 1.5: 1-3.0: 1;
2. the method according to claim 1, wherein the organic solvent is one or more selected from the group consisting of alcohols, ethers, esters, aromatic hydrocarbons, haloalkanes, nitriles, DMSO and DMF;
and/or the volume-mass ratio of the organic solvent to the compound B is 5-15 mL/g;
and/or the tertiary amine is one or more of triethylamine, diisopropylethylamine, DBU and piperidine;
and/or the molar ratio of the tertiary amine to the compound B is 5-10 percent;
and/or the molar ratio of the orthoesters compound to the compound B is 1.6: 1-1.8: 1;
and/or the temperature of the condensation reaction is 75-80 ℃;
and/or the post-treatment method of the condensation reaction is to concentrate the reaction liquid to obtain the crude product of the compound C so as to directly carry out the next reaction.
3. The method according to claim 2, wherein the organic solvent is a nitrile solvent or an ether solvent;
and/or the volume-mass ratio of the organic solvent to the compound B is 8-10 mL/g;
and/or the post-treatment method of the condensation reaction is to cool the reaction product to 30-40 ℃ and then concentrate the reaction product to obtain the crude product of the compound C so as to directly carry out the next reaction.
4. The method according to claim 3, wherein when the organic solvent is a nitrile solvent, the nitrile solvent is acetonitrile.
5. A preparation method of brinzolamide comprises the following steps: a) under the anhydrous condition, in an organic solvent and in the presence of tertiary amine, carrying out condensation reaction on the compound B and an orthoester compound at 70-80 ℃ to obtain a compound C; wherein the orthoesters compound is one or more of trimethyl orthoacetate, triethyl orthoacetate and trimethyl orthobenzoate; b) carrying out nucleophilic substitution reaction on the compound C and 4-tosyl chloride under the action of an acid-binding agent under an anhydrous condition to obtain a compound D; c) carrying out amination reaction on the compound D and an ethylamine water solution to obtain brinzolamide shown in the formula A;
wherein the specific reaction conditions and parameters of the condensation reaction are as defined in claim 1 or 2.
6. The preparation method of claim 5, wherein the reaction solution of the condensation reaction is cooled to 30-40 ℃, then concentrated to obtain the crude compound C, and the reactions in the steps b) and C) are continued, and after the amination reaction is completed, the post-treatment mode comprises the following steps: acidifying the reaction system by using concentrated hydrochloric acid until the pH value is 1-5, and extracting by using an organic solvent; combining organic phases and extracting with dilute hydrochloric acid; and combining the extracted water phases, adding alkali to adjust the pH to 7-8, stirring, filtering the precipitate, and drying.
7. The preparation method according to claim 6, wherein before the post-treatment after the amination reaction is completed, the ethylamine in the amination reaction system is steamed out, and the mixture is distilled and concentrated until the volume-mass ratio of the amination reaction system to the compound B is 7-8 mL/g, and then the temperature is reduced to-5-0 ℃;
and/or dripping concentrated hydrochloric acid at the temperature of 20-30 ℃;
and/or the final point of acidification is pH of 1-2;
and/or after the acidification is finished, adding 0.1-0.4 mL/g of concentrated hydrochloric acid, and stirring for 1-2 h at the temperature of 20-30 ℃; the volume mass ratio of the concentrated hydrochloric acid to the compound B is 0.1-0.4 mL/g;
and/or the organic solvent is methyl tert-butyl ether and/or ethyl acetate;
and/or the volume-mass ratio of the organic solvent to the compound B is 5 mL/g;
and/or, extracting twice with said organic solvent;
and/or the concentration of the dilute hydrochloric acid is 1-2N;
and/or the volume-mass ratio of the dilute hydrochloric acid to the compound B is 2 mL/g;
and/or the alkali adding mode is as follows: adding sodium bicarbonate solid to adjust the pH value to 5-6; adding water and a saturated sodium bicarbonate solution to adjust the pH value to 7-8; wherein the volume-mass ratio of the water to the compound B is 3-6 mL/g; the sodium bicarbonate solids and the saturated sodium bicarbonate solution are used in amounts to achieve the desired pH.
8. The preparation method according to claim 6, wherein after the filtration is finished, the filtrate is further recovered and purified, the recovered organic solvent is a mixed solvent of dichloromethane and methanol with a ratio of 10:1, and the volume mass ratio of the recovered organic solvent to the compound B is 4-8 mL/g; the obtained crude product is recovered and further purified under the condition that ethyl acetate is used for thermal dissolution and recrystallization; wherein the volume-mass ratio of the ethyl acetate to the crude product is 2-5 mL/g.
9. The preparation method according to claim 8, wherein the volume-to-mass ratio of the organic solvent used for recovery to the compound B is 5 to 6 mL/g;
and/or the volume-mass ratio of the ethyl acetate to the crude product is 2-3 mL/g.
10. The method for preparing brinzolamide as claimed in claim 5, wherein said step b) comprises the steps of: under the anhydrous condition, under the action of an acid-binding agent, dripping the solution of 4-tosyl chloride into the solution of the compound C to carry out nucleophilic substitution reaction to prepare a compound D;
and/or, the step c) comprises the following steps: and (3) carrying out amination reaction on 70% of ethylamine water solution and the compound D at 10-20 ℃ to obtain brinzolamide shown in the formula A.
11. The method according to claim 10, wherein in the step b), the solvent in the solution of the compound C is ether or halogenated alkane; and/or in the step b), the volume-to-mass ratio of the solvent to the compound C in the solution of the compound C is 2-6 mL/g;
and/or in the step b), the acid-binding agent is a tertiary amine organic base with the alkalinity stronger than that of the C hydroxyl site of the compound;
and/or in the step b), the molar ratio of the acid-binding agent to the compound C is 1.0: 1-3.0: 1;
and/or in the step b), the acid-binding agent is added directly or dropwise, and the temperature of the system is guaranteed to be-10-0 ℃; and/or in the step b), the reaction temperature of the nucleophilic substitution reaction is-5 ℃;
and/or in the step b), in the solution of the 4-tosyl chloride, the solvent is ether or halogenated alkane;
and/or in the step b), in the solution of 4-tosyl chloride, the volume-to-mass ratio of the solvent to the 4-tosyl chloride is 1-3 mL/g;
and/or in the step b), the dropping speed of the solution of the 4-tosyl chloride is 1-3 d/s;
and/or in the step c), the dropping speed of the 70% ethylamine water solution is 1-5 d/s at-5-10 ℃;
and/or in the step c), the molar ratio of the ethylamine in the 70% ethylamine water solution to the compound D is 20: 1-40: 1;
and/or in the step c), the reaction temperature of the amination reaction is 15-20 ℃.
12. The method of claim 11, wherein in step b), the solvent of the solution of compound C is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and dichloromethane;
and/or in the step b), the volume-to-mass ratio of the solvent to the compound C in the solution of the compound C is 4-5 mL/g;
and/or in the step b), the acid-binding agent is one of pyridine, triethylamine, diisopropylethylamine and DMAP;
and/or in the step b), the molar ratio of the acid-binding agent to the compound C is 2.5: 1-3.0: 1;
and/or in the step b), the acid-binding agent is added dropwise at a dropping speed of 1d/s at the temperature of-10-0 ℃;
and/or in the step b), the reaction temperature of the nucleophilic substitution reaction is-5-0 ℃;
and/or, in the step b), in the solution of 4-tosyl chloride, the solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and dichloromethane;
and/or in the step b), the volume-to-mass ratio of the solvent to the 4-tosyl chloride in the solution of the 4-tosyl chloride is 2 mL/g;
and/or in the step b), the dropping speed of the solution of the 4-tosyl chloride is 1-2 d/s;
and/or in the step c), the dropping speed of the 70% ethylamine water solution is 1-3 d/s at 0-5 ℃;
and/or, in the step c), the molar ratio of the ethylamine in the 70% aqueous solution of the ethylamine to the compound D is 40: 1.
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