CN114560779A - Synthesis method of mirabegron key intermediate - Google Patents
Synthesis method of mirabegron key intermediate Download PDFInfo
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- CN114560779A CN114560779A CN202210090134.1A CN202210090134A CN114560779A CN 114560779 A CN114560779 A CN 114560779A CN 202210090134 A CN202210090134 A CN 202210090134A CN 114560779 A CN114560779 A CN 114560779A
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- 229960001551 mirabegron Drugs 0.000 title claims abstract description 30
- PBAPPPCECJKMCM-IBGZPJMESA-N mirabegron Chemical compound S1C(N)=NC(CC(=O)NC=2C=CC(CCNC[C@H](O)C=3C=CC=CC=3)=CC=2)=C1 PBAPPPCECJKMCM-IBGZPJMESA-N 0.000 title claims abstract description 30
- 238000001308 synthesis method Methods 0.000 title claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 102000004190 Enzymes Human genes 0.000 claims abstract description 23
- 108090000790 Enzymes Proteins 0.000 claims abstract description 23
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 75
- 239000000047 product Substances 0.000 claims description 55
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 239000007795 chemical reaction product Substances 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- 238000000605 extraction Methods 0.000 claims description 18
- 239000002841 Lewis acid Substances 0.000 claims description 16
- 150000007517 lewis acids Chemical class 0.000 claims description 16
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000003638 chemical reducing agent Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 238000006722 reduction reaction Methods 0.000 claims description 14
- UHUUYVZLXJHWDV-UHFFFAOYSA-N trimethyl(methylsilyloxy)silane Chemical group C[SiH2]O[Si](C)(C)C UHUUYVZLXJHWDV-UHFFFAOYSA-N 0.000 claims description 13
- 238000006482 condensation reaction Methods 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 11
- 239000012024 dehydrating agents Substances 0.000 claims description 11
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 10
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 229960003424 phenylacetic acid Drugs 0.000 claims description 8
- 239000003279 phenylacetic acid Substances 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 5
- LNJUVOPKIUQOQK-UHFFFAOYSA-N (4-nitrophenyl)azanium;chloride Chemical compound Cl.NC1=CC=C([N+]([O-])=O)C=C1 LNJUVOPKIUQOQK-UHFFFAOYSA-N 0.000 claims description 4
- JVMHULJEYUQYSH-UHFFFAOYSA-N 2-(4-nitrophenyl)ethylazanium;chloride Chemical compound Cl.NCCC1=CC=C([N+]([O-])=O)C=C1 JVMHULJEYUQYSH-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 238000003912 environmental pollution Methods 0.000 abstract description 8
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 4
- AWMVMTVKBNGEAK-QMMMGPOBSA-N (R)-styrene oxide Chemical compound C1O[C@@H]1C1=CC=CC=C1 AWMVMTVKBNGEAK-QMMMGPOBSA-N 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000001035 drying Methods 0.000 description 10
- 239000010410 layer Substances 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 206010020853 Hypertonic bladder Diseases 0.000 description 7
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 7
- 208000020629 overactive bladder Diseases 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- GDVABISCIUUZOH-UHFFFAOYSA-N 1-methoxy-4-nitrobenzene;hydrochloride Chemical compound Cl.COC1=CC=C([N+]([O-])=O)C=C1 GDVABISCIUUZOH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000711 cancerogenic effect Effects 0.000 description 2
- 231100000315 carcinogenic Toxicity 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000006103 sulfonylation Effects 0.000 description 2
- 238000005694 sulfonylation reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 102000017925 CHRM3 Human genes 0.000 description 1
- 101150060249 CHRM3 gene Proteins 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000808 adrenergic beta-agonist Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000016959 beta-3 Adrenergic Receptors Human genes 0.000 description 1
- 108010014502 beta-3 Adrenergic Receptors Proteins 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960002677 darifenacin Drugs 0.000 description 1
- HXGBXQDTNZMWGS-RUZDIDTESA-N darifenacin Chemical compound C=1C=CC=CC=1C([C@H]1CN(CCC=2C=C3CCOC3=CC=2)CC1)(C(=O)N)C1=CC=CC=C1 HXGBXQDTNZMWGS-RUZDIDTESA-N 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 229960004045 tolterodine Drugs 0.000 description 1
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
- 229940126158 β3 adrenergic receptor agonist Drugs 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a synthesis method of a mirabegron key intermediate, which avoids the use of borane tetrahydrofuran and DMI, reduces environmental pollution, reduces safety risk and reduces production cost; the chiral hydroxyl is obtained by replacing chiral resolution with enzyme catalysis, so that the selectivity is higher, the conversion rate is higher, the cost is relatively lower, and the chiral purity is relatively higher. Avoids the use of expensive R-styrene oxide, has lower production cost and is more suitable for industrialization.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of a mirabegron key intermediate.
Background
Mirabegron is a drug used to treat overactive bladder (OAB) in adults. And currently used remedies for overactive bladder, such as anticholinergic drugs tolterodine and darifenacin, which have the effect of treating OAB by blocking the binding of acetylcholine to M3 receptor, thereby alleviating bladder smooth muscle contraction, mirabegron improves bladder storage capacity by activating β 3 adrenergic receptor in bladder detrusor muscle, thereby alleviating the symptoms of overactive bladder without affecting the function of bladder micturition. The mirabegron is a beta 3 adrenergic receptor agonist therapeutic drug for treating OAB firstly, and the mirabegron successfully comes into the market, and fills up a gap of beta adrenergic receptor agonists in the OAB aspect.
The current R) -2-hydroxy-N- [ [2- (4-nitrophenyl) ethyl ] amino ] -1-phenylethanol monohydrochloride synthetic route suffers from the following drawbacks: the cost is relatively high, the reaction is violent when meeting water and the flammable gas is discharged, the eye, the skin and the respiratory system are stimulated, the operation personnel and the ecological environment are not favored, the mixed solvent is not easy to recover, and the production and post-treatment cost is increased.
Disclosure of Invention
This section is for the purpose of summarizing some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. In this section, as well as in the abstract and the title of the invention of this application, simplifications or omissions may be made to avoid obscuring the purpose of the section, the abstract and the title, and such simplifications or omissions are not intended to limit the scope of the invention.
The present invention has been made in view of the above-mentioned technical drawbacks.
The invention provides a synthesis method of a mirabegron key intermediate, which comprises the following steps,
(1) condensation reaction: reacting phenylacetic acid serving as a starting material with p-nitroaniline hydrochloride in an organic solvent in the presence of an acid-binding agent and a dehydrating agent at the reaction temperature of 4-40 ℃ for 4-24 h to obtain a product I; wherein the molar ratio of the phenylacetic acid to the p-nitrophenylethylamine hydrochloride is 1-1.1: 1;
(2) Enzyme-catalyzed reaction: adding ammonium formate, EW1309-HE enzyme and EW1310-HG enzyme into a reaction solvent of the reaction product I, adjusting the pH to 8-9 by using sodium hydroxide, reacting at the temperature of 25-35 ℃ for 12-24 h, and adding an extraction solvent to extract to obtain a solution of a product II; wherein the molar ratio of the product I to the ammonium formate is 1-5; the solvent is a mixed solvent of isopropanol and water, and a product I: water: the weight volume ratio of isopropanol is 1: (2-8): (1-5);
(3) reduction reaction: and adding Lewis acid into the solution of the product II, dropwise adding a reducing agent, and reacting at the temperature of 40-70 ℃ for 12-36 h to obtain a product III.
As a preferable scheme of the synthesis method of the mirabegron key intermediate, in the step (1), the molar ratio of the acetophenone acid to the dehydrating agent is 1-1.1: 1, and the dehydrating agent is EDC.HCl.
As a preferable embodiment of the synthesis method of the mirabegron key intermediate, in the step (2), the extraction solvent is selected from one of dichloromethane and chloroform.
As a preferable scheme of the synthesis method of the mirabegron key intermediate, the molar ratio of the product II to the Lewis acid is 1: 2-3, wherein the Lewis acid is one of aluminum trichloride or ferric trichloride; the molar ratio of the product II to the reducing agent is 1: 2.5 to 3.5, wherein the reducing agent is tetramethyldisiloxane.
As a preferable scheme of the synthesis method of the mirabegron key intermediate, in the step (1), the reaction temperature is 20-30 ℃.
As a preferable scheme of the synthesis method of the mirabegron key intermediate, in the step (2), the weight-volume ratio of the product I to the extraction solvent is 1: 5 to 10.
As a preferable scheme of the synthesis method of the mirabegron key intermediate, in the step (3), the molar ratio of the product II to the lewis acid is 1: 2-3, wherein the Lewis acid is one of aluminum trichloride or ferric trichloride and the like.
As a preferable scheme of the synthesis method of the mirabegron key intermediate, in the step (3), the molar ratio of the product II to the reducing agent is 1: 2.5 to 3.5, wherein the reducing agent is tetramethyldisiloxane.
As a preferable embodiment of the synthesis method of the mirabegron key intermediate, in the step (1), the weight volume ratio of the acetophenone acid to the organic solvent is 1: 4-10, wherein the organic solvent is one selected from dimethylformamide and dichloromethane.
As a preferable scheme of the synthesis method of the mirabegron key intermediate, in the step (1), the molar ratio of the acetophenone acid to the acid-binding agent is 1-1.1: 1, the acid-binding agent is triethylamine.
The invention has the beneficial effects that: the method avoids the use of borane tetrahydrofuran and DMI, reduces environmental pollution, reduces safety risk and reduces production cost; the chiral hydroxyl is obtained by replacing chiral resolution with enzyme catalysis, so that the selectivity is higher, the conversion rate is higher, the cost is relatively lower, and the chiral purity is relatively higher.
Avoids the use of expensive R-styrene oxide, has lower production cost and is more suitable for industrialization.
The use of sulfonylation reagent is avoided, the environmental pollution is reduced, the development difficulty is reduced, the requirement on the control of the production process is met, the cost control is facilitated, and the industrial production is facilitated.
The invention avoids the use of expensive reagents, dangerous reagents and reagents containing carcinogenic warning structures, obtains chirality by enzyme catalysis, is more environment-friendly in process, adopts a cheap and safe reduction system of Lewis acid and tetramethyldisiloxane to replace borane tetrahydrofuran for reduction reaction, further reduces safety risks, can recycle reaction and extraction solvent, obviously reduces environmental pollution, does not need separation and drying between three steps of reaction, only needs the last step of separation and drying, obviously improves yield, ensures that the total yield of the three steps of reaction exceeds 87%, ensures that the purity of the obtained product is more than 99.5%, and ensures that chiral impurities are less than 0.1%.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without inventive exercise. Wherein:
FIG. 1 is a synthesis route diagram of a key intermediate of mirabegron of the present invention.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with examples are described in detail below.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
Furthermore, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
The invention provides a preparation method of a mirabegron key intermediate R) -2-hydroxy-N- [ [2- (4-nitrophenyl) ethyl ] amino ] -1-phenylethanol monohydrochloride, which is safe and reliable, has little environmental pollution, less by-products, high product purity and low cost. Using phenylacetic acid as initial material, condensing with p-nitrophenylethylamine hydrochloride, reducing ketone into chiral hydroxyl group with biological enzyme, and removing oxygen on amide with tetramethyl disiloxane as new type reducing agent.
(1) Condensation reaction: reacting phenylacetic acid serving as a starting material with p-nitroaniline hydrochloride in an organic solvent in the presence of an acid-binding agent and a dehydrating agent at the reaction temperature of 0-40 ℃ for 4-24 h, and completely reacting to obtain a product I;
wherein:
the molar ratio of the phenylacetic acid to the p-nitrophenylethylamine hydrochloride is 1-1.1: 1
The molar ratio of the acetophenone acid to the dehydrating agent is 1-1.1: 1, and the dehydrating agent is EDC.HCl;
the molar ratio of the acetophenone acid to the acid-binding agent is 1-1.1: 1, and the acid-binding agent is triethylamine or other organic amines.
The weight to volume ratio of starting material to organic solvent (i.e., g/ml) was 1: 4-10, wherein the organic solvent is one selected from dimethylformamide and dichloromethane.
(2) Enzyme-catalyzed reaction: adding ammonium formate, EW1309-HE enzyme and EW1310-HG enzyme into the reaction product I in a reaction solvent, adjusting the pH to 8-9 by using sodium hydroxide, reacting at the temperature of 25-35 ℃ for 12-24 h, completely reacting, recovering the reaction solvent, and adding an extraction solvent to extract to obtain a solution of a product II;
wherein:
the molar ratio of the product I to the ammonium formate is 1-5, and the dosage of the enzyme is proper.
The weight to volume ratio of product I to reaction solvent (i.e., g/ml) was 1: 2-8: 1-5 (product I: water: isopropanol), wherein the solvent is a mixed solvent of isopropanol and water.
The weight to volume ratio of product I to extraction solvent (i.e., g/ml) was 1: 5-10, wherein the solvent is one selected from dichloromethane, chloroform and the like.
(3) Reduction reaction: adding Lewis acid into the solution of the reaction product II, dropwise adding a reducing agent, reacting at 40-70 ℃ for 12-36 h, and reacting completely to obtain a product III;
wherein:
the molar ratio of product II to Lewis acid is 1: 2-3, wherein the Lewis acid is one of aluminum trichloride or ferric trichloride and the like.
The molar ratio of the product II to the reducing agent is 1: 2.5 to 3.5, wherein the reducing agent is tetramethyldisiloxane.
The reaction product III is subjected to extraction, salification and crystallization to obtain the product.
In the step (1), in the presence of an acid-binding agent and a dehydrating agent, the phenylacetic acid and the p-nitroaniline hydrochloride are subjected to condensation reaction, and after the reaction is finished, the product I is obtained by extraction, washing and concentration.
According to the enzymatic reaction in the step (2), a product I is dissolved, ammonium formate, EW1309-HE enzyme and EW1310-HG enzyme are added, the pH is adjusted to 8-9, after the reaction is finished, a solvent is concentrated and recycled, dichloromethane or chloroform is added for extraction, and drying is carried out to obtain a product II.
In the reduction reaction in the step (3), aluminum trichloride or ferric trichloride is added into a solution of a product II, tetramethyldisiloxane is dropwise added, the temperature is raised, the reflux reaction is complete, the temperature is reduced, the product is filtered, washed and dried, and the purity of the obtained product is more than 99 percent and the chiral impurity is less than 0.1 percent.
The process route of the invention is as follows:
example 1:
condensation reaction to prepare reaction product I:
initial raw materials: acetophenone acid, 30g (about 0.2 mol);
organic solvent: this example was selected from dichloromethane 150 ml;
dehydrating agent: EDC.HCl (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride) 36g (0.2mol) was chosen for this example;
acid binding agent: this example is selected from triethylamine 20.2g (about 0.2 mol);
The condensation reaction process comprises the following steps: 30g (about 0.2mol) of initial raw material acetophenone acid and 33.4g (about 0.2mol) of p-nitroanisole hydrochloride are added into a reaction bottle, temperature is controlled to be 25 ℃, 150ml of dichloromethane is added, 20.2g (about 0.2mol) of triethylamine is added dropwise, 36g (0.2mol) of EDC.HCl is added, the reaction is kept for about 6 hours, 100ml of water is added, extraction and layering are carried out, 100ml of water is added into a dichloromethane layer for washing, layering is carried out, the dichloromethane layer is concentrated to be dry, about 57.8g (about 0.194mol) of reaction product I is obtained, the yield is 97 percent, and the reaction product is used for the next step of reaction.
Preparing a reaction product II by enzyme catalysis reaction:
raw material 1: reaction product I57.8 g (about 0.194 mol);
raw material 2: 2g of ammonium formate;
water: 232ml +232 ml;
reaction solvent: 116ml of isopropanol;
extracting solvent: 448ml of dichloromethane;
EW1309-HE enzyme: 0.08 g;
EW1310-HG enzyme: 0.07 g;
the condensation reaction process comprises the following steps: adding a product I, 232ml of water, 116ml of isopropanol and 2g of ammonium formate into a reaction bottle, adjusting the pH value to 8-9 by using sodium hydroxide, controlling the reaction temperature to be 30 ℃, adding 0.08g of EW1309-HE enzyme and 0.07g of EW1310-HG enzyme, reacting for about 14 hours, filtering after the reaction is completed, concentrating and recovering isopropanol, adding 448ml of dichloromethane for extraction, layering, washing with 232ml of water, adding desiccant anhydrous magnesium sulfate into an organic layer for drying, filtering to obtain a solution of a reaction product II (about 0.186mol), wherein the yield is 95.8%, and the solution is used for the next reaction.
Reduction reaction to prepare the product R) -2-hydroxy-N- [ [2- (4-nitrophenyl) ethyl ] amino ] -1-phenylethanol monohydrochloride:
raw materials: a solution of reaction product II in methylene chloride (about 0.186 mol);
lewis acid: 62g (0.465mol) of aluminum trichloride;
and (3) washing agent: 100ml of dichloromethane;
reducing agent: 70g (0.52mol) of tetramethyldisiloxane;
the reduction reaction process comprises the following steps: adding a dichloromethane solution of the product II into a reaction bottle, adding 62g of aluminum trichloride, dropwise adding 70g of tetramethyldisiloxane, heating to 40 ℃, keeping the temperature for reaction for 16h, cooling to 25 ℃, dropwise adding 22g of hydrochloric acid, keeping the temperature for 1 h, filtering, washing with 100ml of dichloromethane, and drying to obtain 57g of the product, wherein the purity of the product is more than 99.5%, the chiral impurity is less than or equal to 0.1%, and the yield of the step is 94.6%.
Comparative example 1:
condensation reaction to prepare reaction product I:
the condensation reaction process comprises the following steps: a reaction flask was charged with 30g (about 0.2mol) of starting material acetophenone acid and 33.4g (about 0.2mol) of p-nitroanisole hydrochloride, temperature was controlled at 25 ℃, 150ml of dichloromethane was added, 20.2g (about 0.2mol) of triethylamine was added dropwise, 25.2g (0.2mol) of DIC (diisopropylcarbodiimide) was added thereto, the reaction was maintained for about 6 hours, 100ml of water was added thereto, extraction and layer separation were performed, 100ml of water was added to the dichloromethane layer, and the dichloromethane layer was washed with water and layer separation and concentrated to dryness to obtain about 47.7g (about 0.16mol) of a reaction product I, with a yield of 80%.
Comparative example 2:
condensation reaction to prepare a reaction product I:
the condensation reaction process comprises the following steps: 30g (about 0.2mol) of initial raw material acetophenone acid and 33.4g (about 0.2mol) of p-nitroanisole hydrochloride are added into a reaction bottle, the temperature is controlled to be 25 ℃, 150ml of ethyl acetate is added, 20.2g (about 0.2mol) of triethylamine is added dropwise, 36g (0.2mol) of EDC.HCl is added, the reaction is kept for about 6 hours, 100ml of water is added, extraction and layering are carried out, 100ml of water is added into an ethyl acetate layer, the ethyl acetate layer is washed and layered, and the ethyl acetate layer is concentrated to be dry to obtain about 50.6g (about 0.17mol) of reaction product I, wherein the yield is 85%.
Comparative example 3:
preparing a reaction product II by enzyme catalysis reaction:
the condensation reaction process comprises the following steps: adding 0.2mol of product I, 232ml of water, 150ml of methanol and 2g of ammonium formate into a reaction bottle, adjusting the pH value to 8-9 by using sodium hydroxide, controlling the reaction temperature to be 30 ℃, adding 0.08g of EW1309-HE enzyme and 0.07g of EW1310-HG enzyme, reacting for about 14 hours, filtering after the reaction is completed, concentrating, adding 448ml of dichloromethane for extraction, layering, washing with 232ml of water, adding desiccant anhydrous magnesium sulfate into an organic layer, drying, concentrating to obtain a reaction product II (about 0.15mol), wherein the yield is 75%, and using the reaction product II for the next reaction.
Comparative example 4:
reduction reaction to prepare the product R) -2-hydroxy-N- [ [2- (4-nitrophenyl) ethyl ] amino ] -1-phenylethanol monohydrochloride:
The reduction reaction process comprises the following steps: adding 0.186mol of dichloromethane solution of the product II into a reaction bottle, adding 62g of aluminum trichloride, dropwise adding 70g of tetramethyldisiloxane, heating to 20 ℃, keeping the temperature for reaction for 16h, dropwise adding 22g of hydrochloric acid, keeping the temperature for 1 h, filtering, washing with 100ml of dichloromethane, and drying to obtain 40g of product, wherein the purity of the product is 96%, the chiral impurity content is less than or equal to 0.1%, and the yield of the step is 66.4%.
Comparative example 5:
reduction reaction to prepare the product R) -2-hydroxy-N- [ [2- (4-nitrophenyl) ethyl ] amino ] -1-phenylethanol monohydrochloride:
the reduction reaction process comprises the following steps: adding 0.186mol of dichloromethane solution of the product II into a reaction bottle, adding 62g of aluminum trichloride, dropwise adding 35g of tetramethyldisiloxane, heating to 40 ℃, keeping the temperature for reaction for 16h, dropwise adding 22g of hydrochloric acid, keeping the temperature for 1 h, filtering, washing with 100ml of dichloromethane, and drying to obtain 45g of product, wherein the purity of the product reaches 96.5%, the chiral impurity is less than or equal to 0.1%, and the yield of the step is 74.7%.
The method avoids the use of borane tetrahydrofuran and DMI, reduces environmental pollution, reduces safety risk and reduces production cost; the chiral hydroxyl is obtained by replacing chiral resolution with enzyme catalysis, so that the selectivity is higher, the conversion rate is higher, the cost is relatively lower, and the chiral purity is relatively higher. Avoids the use of expensive R-styrene oxide, has lower production cost and is more suitable for industrialization. The use of sulfonylation reagent is avoided, the environmental pollution is reduced, the development difficulty is reduced, the requirement on the control of the production process is met, the cost control is facilitated, and the industrial production is facilitated. The invention avoids the use of expensive reagents, dangerous reagents and reagents containing carcinogenic warning structures, obtains chirality by enzyme catalysis, is more environment-friendly in process, adopts a cheap and safe reduction system of Lewis acid and tetramethyldisiloxane to replace borane tetrahydrofuran for reduction reaction, further reduces safety risks, can recycle reaction and extraction solvent, obviously reduces environmental pollution, does not need separation and drying between three steps of reaction, only needs the last step of separation and drying, obviously improves yield, ensures that the total yield of the three steps of reaction exceeds 87%, ensures that the purity of the obtained product is more than 99.5%, and ensures that chiral impurities are less than 0.1%.
It should be noted that the above-mentioned embodiments are only for illustrating the technical solutions of the present invention and not for limiting, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, which should be covered by the claims of the present invention.
Claims (10)
1. A synthesis method of a mirabegron key intermediate is characterized by comprising the following steps: the method comprises the following steps of (1),
(1) condensation reaction: reacting phenylacetic acid serving as a starting material with p-nitroaniline hydrochloride in an organic solvent in the presence of an acid-binding agent and a dehydrating agent at the reaction temperature of 4-40 ℃ for 4-24 h to obtain a product I; wherein the molar ratio of the phenylacetic acid to the p-nitrophenylethylamine hydrochloride is 1-1.1: 1;
(2) enzyme-catalyzed reaction: adding ammonium formate, EW1309-HE enzyme and EW1310-HG enzyme into a reaction solvent of the reaction product I, adjusting the pH to 8-9 by using sodium hydroxide, reacting at the temperature of 25-35 ℃ for 12-24 h, and adding an extraction solvent to extract to obtain a solution of a product II; wherein the molar ratio of the product I to the ammonium formate is 1-5; the solvent is a mixed solvent of isopropanol and water, and a product I: water: the weight volume ratio of isopropanol is 1: (2-8): (1-5);
(3) Reduction reaction: and adding Lewis acid into the solution of the product II, dropwise adding a reducing agent, and reacting at the temperature of 40-70 ℃ for 12-36 h to obtain a product III.
2. The synthesis method of the mirabegron key intermediate as claimed in claim 1, which is characterized in that: in the step (1), the molar ratio of the acetophenone acid to the dehydrating agent is 1-1.1: 1, and the dehydrating agent is EDC.HCl.
3. The synthesis method of the mirabegron key intermediate according to claim 1 or 2, which is characterized in that: in the step (2), the extraction solvent is selected from one of dichloromethane and chloroform.
4. The synthesis method of the mirabegron key intermediate according to claim 1 or 2, which is characterized in that: the molar ratio of product II to Lewis acid is 1: 2-3, wherein the Lewis acid is one of aluminum trichloride or ferric trichloride; the molar ratio of the product II to the reducing agent is 1: 2.5 to 3.5, wherein the reducing agent is tetramethyldisiloxane.
5. The synthesis method of the mirabegron key intermediate according to claim 1 or 2, which is characterized in that: in the step (1), the reaction temperature is 20-30 ℃.
6. The synthesis method of the mirabegron key intermediate according to claim 1 or 2, which is characterized in that: in the step (2), the weight-to-volume ratio of the product I to the extraction solvent is 1: 5 to 10.
7. The synthesis method of the mirabegron key intermediate according to claim 1 or 2, which is characterized in that: in the step (3), the molar ratio of the product II to the Lewis acid is 1: 2-3, wherein the Lewis acid is one of aluminum trichloride or ferric trichloride and the like.
8. The synthesis method of the mirabegron key intermediate according to claim 1 or 2, which is characterized in that: in the step (3), the molar ratio of the product II to the reducing agent is 1: 2.5 to 3.5, wherein the reducing agent is tetramethyldisiloxane.
9. The synthesis method of the mirabegron key intermediate according to claim 1 or 2, which is characterized in that: in the step (1), the weight volume ratio of the acetophenone acid to the organic solvent is 1: 4-10, wherein the organic solvent is one selected from dimethylformamide and dichloromethane.
10. The synthesis method of the mirabegron key intermediate according to claim 1 or 2, which is characterized in that: in the step (1), the molar ratio of the acetophenone acid to the acid-binding agent is 1-1.1: 1, the acid-binding agent is triethylamine.
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