CN115403509A - Preparation method of lefenacin intermediate - Google Patents
Preparation method of lefenacin intermediate Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- -1 1-benzyl piperidine-4-yl [1,1' -biphenyl ] -2-yl Chemical group 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 16
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical compound NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 123
- 238000006243 chemical reaction Methods 0.000 claims description 71
- 239000000543 intermediate Substances 0.000 claims description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 230000001276 controlling effect Effects 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 20
- 230000001105 regulatory effect Effects 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 230000002829 reductive effect Effects 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 18
- 239000000706 filtrate Substances 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 13
- 239000012074 organic phase Substances 0.000 claims description 11
- 239000008213 purified water Substances 0.000 claims description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000007098 aminolysis reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000012948 isocyanate Substances 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 150000002513 isocyanates Chemical class 0.000 abstract 1
- 239000008346 aqueous phase Substances 0.000 description 27
- 239000000243 solution Substances 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- BPPZXJZYCOETDA-UHFFFAOYSA-N 1-benzylpiperidin-4-ol Chemical compound C1CC(O)CCN1CC1=CC=CC=C1 BPPZXJZYCOETDA-UHFFFAOYSA-N 0.000 description 7
- MSHSHVZVLWLNIO-UHFFFAOYSA-N (1-benzylpiperidin-4-yl) n-(2-phenylphenyl)carbamate Chemical compound C1CN(CC=2C=CC=CC=2)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 MSHSHVZVLWLNIO-UHFFFAOYSA-N 0.000 description 4
- IHHUGFJSEJSCGE-UHFFFAOYSA-N 1-isocyanato-2-phenylbenzene Chemical compound O=C=NC1=CC=CC=C1C1=CC=CC=C1 IHHUGFJSEJSCGE-UHFFFAOYSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 2
- 238000006197 hydroboration reaction Methods 0.000 description 2
- 238000011418 maintenance treatment Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- FYDWDCIFZSGNBU-UHFFFAOYSA-N [1-[2-[[4-[(4-carbamoylpiperidin-1-yl)methyl]benzoyl]-methylamino]ethyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C=1C=C(CN2CCC(CC2)C(N)=O)C=CC=1C(=O)N(C)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 FYDWDCIFZSGNBU-UHFFFAOYSA-N 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
- 230000001154 acute effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- ULSOLOBYKJRHGB-UHFFFAOYSA-N benzyl n-methyl-n-(2-oxoethyl)carbamate Chemical compound O=CCN(C)C(=O)OCC1=CC=CC=C1 ULSOLOBYKJRHGB-UHFFFAOYSA-N 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 230000007885 bronchoconstriction Effects 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 210000005037 parasympathetic nerve Anatomy 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 229950000150 revefenacin Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a lefenacin intermediate. According to the method, phenyl chloroformate is used for acylating 1-benzyl piperidine-4-alcohol to prepare an intermediate I-1, and [1,1 '-biphenyl ] -2-amine is used for aminolysis of the intermediate I-1 to prepare a target compound 1-benzyl piperidine-4-yl [1,1' -biphenyl ] -2-yl carbamate. The method avoids using virulent isocyanate reagent, has simple synthetic route, more convenient operation and higher yield, and is more suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a lefenacin intermediate.
Background
Raffinacin (Revefenacin), chemical name 1- (2- (4- ((4-carbamoylpiperidin-1-yl) methyl) -N-methylbenzamido) ethylpiperidin-4-yl [1,1' -biphenyl]-2-ylcarbamate, a novel long-acting anticholinergic drug approved for marketing in the united states by 11/9.2018, first discovered by Theravance biopharmaceutical corporation in ireland and developed in combination with Mylan pharmaceuticals in the united states, trade name
Rafenacin is a long-acting muscarinic receptor antagonist, which is activated by interaction with M on bronchial smooth muscle 3 Muscarinic receptor binding inhibits the bronchoconstriction caused by acetylcholine release from parasympathetic nerve terminals. The traditional Chinese medicine composition is mainly used for the maintenance treatment of Chronic Obstructive Pulmonary Disease (COPD) clinically, and comprises the maintenance treatment of chronic bronchitis and emphysema accompanied by dyspnea and the prevention of acute attack. The chemical structural formula is as follows:
the literature reports on the synthetic method of rafenicin are less, and the synthetic route is mainly focused on Chinese patents CN1759108A, CN1882556A, CN1930125B, CN102958916B, US20050203133Al and J.Med.chem.,2015,58 (6), 2609-2622 disclosed by original research company, wherein the classical route is that 2-diphenyl isocyanate (2) is used as a starting material, 1-benzylpiperidine-4-ol (3) is firstly reacted to prepare 1-benzylpiperidine-4-yl [1,1' -biphenyl ] -2-yl carbamate, then the benzyl group is removed to obtain piperidine-4-yl [1,1' -biphenyl ] -2-yl carbamate (4), the obtained product is then reacted with benzyl methyl (2-oxoethyl) carbamate through sodium triacetoxyborohydride, the debenzyloxycarbonyl group is removed to generate 1- (2- (methylamino) ethyl) piperidine-4-yl [1,1' -biphenyl ] -2-yl carbamate (5), and the obtained product is finally subjected to reduction and hydroboration with sodium p-formylamide to obtain the target product through hydroboration of 1- (2- (methylamino) ethyl) piperidine-4-yl-2-yl carbamate (5). The relevant reaction scheme is as follows:
however, the above process has the following problems: (1) by adopting a linear synthesis strategy, the reaction steps are longer, most intermediates in the reactions in each step are oily liquid with lower melting point, so that the intermediates are difficult to purify, impurities are easy to carry, the yield of target products is low, the production cost is higher, and the industrialization difficulty is higher; (2) in the subsequent two-step reductive amination, the moisture content of the material also leads to a serious decrease in yield and even failure of the reaction.
From the above, 1-benzylpiperidin-4-yl [1,1 '-biphenyl ] -2-ylcarbamate is known to be a key intermediate for the preparation of ralfinacin, and thus 1-benzylpiperidin-4-yl [1,1' -biphenyl ] -2-ylcarbamate may directly affect the production, market supply and quality problems of the drug. The specific structural formula is as follows:
however, in the above process, when 1-benzylpiperidin-4-yl [1,1 '-biphenyl ] -2-ylcarbamate is prepared, although the yield is about 100%, the used material 2-biphenylyl isocyanate (2) has high activity and high price of about 17000 yuan/kg, and the other material 1-benzylpiperidin-4-ol (3) has a water content of about 0.2-0.5% and a low melting point of about 55-60 ℃ and is difficult to dry, so that a large amount of impurities are generated in the reaction, thereby further reducing the yield of a single-step reaction, wherein the content of 1-benzylpiperidin-4-yl [1,1' -biphenyl ] -2-ylcarbamate in the obtained crude product is low and only about 70%, and further purification is required, thereby further reducing the yield and increasing the production cost. The related impurity structures are as follows:
in conclusion, in view of the defects existing in the prior art for preparing 1-benzylpiperidin-4-yl [1,1 '-biphenyl ] -2-yl carbamate, research and search for a preparation process which is simple and safe to operate, mild in reaction conditions, high in product yield and high in purity and is suitable for industrial production of 1-benzylpiperidin-4-yl [1,1' -biphenyl ] -2-yl carbamate still needs to be solved at present.
Disclosure of Invention
Aiming at the problems in the prior art for preparing the leflufenacin intermediate 1-benzylpiperidine-4-yl [1,1 '-biphenyl ] -2-yl carbamate, the invention provides a novel preparation method of 1-benzylpiperidine-4-yl [1,1' -biphenyl ] -2-yl carbamate. The method has mild reaction conditions, safe and simple operation process, and the prepared target product has higher purity and yield.
The invention is realized by the following technical scheme:
a preparation method of a lefenacin intermediate 1-benzylpiperidine-4-yl [1,1' -biphenyl ] -2-yl carbamate comprises the steps of carrying out SM-2 acylation on 1-benzylpiperidine-4-ol to obtain an intermediate I-1, and carrying out aminolysis on the intermediate I-1 by using [1,1' -biphenyl ] -2-amine to obtain a target compound 1-benzylpiperidine-4-yl [1,1' -biphenyl ] -2-yl carbamate, wherein the reaction formula is as follows:
wherein R is H or NO 2 ；
A preparation method of a leflufenacin intermediate 1-benzylpiperidine-4-yl [1,1' -biphenyl ] -2-yl carbamate shown as a formula I comprises the following specific steps:
step 1, adding SM-1 and an acid binding agent into a reaction solvent, and controlling the temperature T 1A Adding SM-2, controlling the temperature T 1B After the reaction is finished, carrying out post-treatment to obtain an intermediate I-1;
preferably, SM-2 described in step 1 is one of phenyl chloroformate or p-nitro phenyl chloroformate, preferably phenyl chloroformate.
Preferably, the acid scavenger described in step 1 includes, but is not limited to, K 2 CO 3 、Na 2 CO 3 One or the combination of triethylamine, N-diisopropylethylamine and pyridine, preferably triethylamine.
Preferably, the reaction solvent in step 1 is one or a combination of dichloromethane and chloroform, preferably dichloromethane.
Preferably, the feeding molar ratio of SM-1 to SM-2 to the acid binding agent in the step 1 is 1.2-3.0: 2.2 to 5.0, preferably 1.6:2.8.
preferably, T is as defined in step 1 1A Is-10 to 10 ℃, preferably 0 to 5 ℃; reaction temperature T 1B Is 15 to 40 ℃, preferably 25 to 30 ℃.
In a preferred embodiment, the post-treatment step in step 1 is: adding purified water into the reaction solution, regulating the pH value of the water phase to 1-3 by hydrochloric acid, separating liquid, continuously washing the water phase by dichloromethane, regulating the pH value of the water phase to 9-10 by sodium hydroxide solution, extracting by an organic solvent, washing the organic phase by saturated saline solution, drying, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dried to obtain the intermediate I-1.
Preferably, the extraction solvent includes, but is not limited to, one or a combination of dichloromethane, chloroform, ethyl acetate, methyl tert-butyl ether, preferably dichloromethane.
And 2, adding the intermediates I-1 and SM-3 into a reaction solvent, controlling the temperature until the reaction is finished, and carrying out post-treatment to obtain the target compound I.
Preferably, the reaction solvent in step 2 is one or a combination of dichloromethane and chloroform, preferably dichloromethane.
Preferably, the feeding molar ratio of I-1 to SM-3 in the step 2 is 1.
Preferably, the reaction temperature in step 2 is 20 to 50 ℃, preferably 30 to 35 ℃.
In a preferred embodiment, the post-treatment step in step 2 is as follows: after the reaction is finished, concentrating the reaction solution under reduced pressure to be dry, and recrystallizing by a dichloromethane-methanol system to obtain a target product I. The volume ratio of the dichloromethane to the methanol is 2-4: 1, preferably 3:1.
the invention has the beneficial effects that:
the invention provides a simple and efficient method for preparing 1-benzylpiperidine-4-yl [1,1' -biphenyl ] -2-yl carbamate as an intermediate of ralfinacin, which takes 1-benzylpiperidine-4-ol as a starting material, is acylated by phenyl chloroformate, and is aminolyzed by [1,1' -biphenyl ] -2-amine to prepare the target compound 1-benzylpiperidine-4-yl [1,1' -biphenyl ] -2-yl carbamate. Although the steps are prolonged, the activity of phenyl chloroformate is lower than that of 2-biphenyl isocyanate, so that the generation of related impurities can be effectively avoided, and the whole synthesis method is simple and convenient to operate and mild in conditions; the target product prepared by the process has higher yield and purity, and is suitable for industrial large-scale production.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
The structure of the compound obtained by the invention is confirmed:
ESI-TOF + -HRMS(m/z):312.1383[M+H] + ； 1 H NMR(600MHz,DMSO-d 6 )δ7.41～7.35(m,2H),7.29～7.19(m,8H),4.95～4.85(m,1H),3.65(s,2H),2.82～2.71(m,2H),2.48～2.38(m,2H),2.31～2.21(m,2H),2.09～1.99(m,2H)； 13 C NMR(151MHz,DMSO-d 6 )δ156.86,152.40,138.23,129.21,128.81,127.95,127.03,126.55,119.76,70.45,63.66,50.79,30.94。
ESI-TOF + -HRMS(m/z):357.1546[M+H] + ； 1 H NMR(600MHz,DMSO-d 6 )δ8.23(d,J＝7.42Hz,2H),7.46(d,J＝7.45Hz,2H),7.29～7.19(m,5H),4.92～4.84(m,1H),3.65(s,2H),2.80～2.72(m,2H),2.48～2.40(m,2H),2.29～2.20(m,2H),2.09～2.00(m,2H)； 13 C NMR(151MHz,DMSO-d 6 )δ157.73,156.04,146.95,138.19,128.76,127.64,126.38,123.25,121.33,70.85,63.48,50.61,30.85。
ESI-TOF + -HRMS(m/z):387.2104[M+H] + ； 1 H NMR(600MHz,DMSO-d 6 )δ8.66(s,1H),7.40～7.42(m,2H),7.35～7.37(m,3H),7.33～7.34(m,2H),7.27～7.32(m,6H),7.23～7.25(m,1H),7.44～7.48(m,1H),3.42(s,2H),2.56(s,2H),2.10～2.13(m,2H),1.72(d,J＝9.78Hz,2H),1.41～1.46(m 2H)； 13 C NMR(151MHz,DMSO-d 6 )δ153.84,139.13,138.37,137.41,134.65,130.13,128.60,128.52,128.13,128.05,127.71,127.03,126.88,126.76,125.95,69.95,61.81,50.12,30.63。
in the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Synthesis of I-1:
example 1
Adding SM-1 (19.13g, 0.10mol) and triethylamine (28.33g, 0.28mol) into dichloromethane (100 ml), controlling the temperature to be 0-5 ℃, adding phenyl chloroformate (SM-2-1, 25.05g, 0.110mol), controlling the temperature to be 25-30 ℃ for reaction, after the detection reaction is finished, adding purified water (500 ml) into a reaction solution, regulating the pH value of an aqueous phase to be 2 by using hydrochloric acid, separating liquid, continuously washing the aqueous phase by using dichloromethane (150 ml multiplied by 2), regulating the pH value of the aqueous phase to be 10 by using a sodium hydroxide solution, extracting dichloromethane (150 ml multiplied by 3), washing an organic phase by using saturated saline (100 ml multiplied by 2), drying by anhydrous sodium sulfate, filtering, concentrating a filtrate to be dry to obtain an intermediate I-1-1, wherein the yield is 96.8% and the purity is 98.5%. The reaction route is as follows:
example 2
SM-1 (19.13g, 0.10mol), K 2 CO 3 (38.70g, 0.28mol) is added into dichloromethane (100 ml), phenyl chloroformate (SM-2-1, 18.79g, 0.12mol) is added at the temperature of 5-10 ℃, the temperature is controlled at 30-35 ℃ for reaction, after the reaction is detected to be finished, purified water (500 ml) is added into reaction liquid, hydrochloric acid is used for adjusting the pH value of an aqueous phase to 2, liquid separation is carried out, the aqueous phase is continuously washed by dichloromethane (150 ml multiplied by 2), the pH value of the aqueous phase is adjusted to 10 by sodium hydroxide solution, dichloromethane (150 ml multiplied by 3) is extracted, an organic phase is washed by saturated saline (100 ml multiplied by 2), anhydrous sodium sulfate is dried, filtration is carried out, filtrate is concentrated under reduced pressure to be dry to obtain an intermediate I-1-1, the yield is 94.7%, and the purity is 98.3%.
Example 3
SM-1 (19.13g, 0.10mol), na 2 CO 3 Adding (29.68g, 0.28mol) into dichloromethane (100 ml), controlling the temperature to be 5-10 ℃, adding phenyl chloroformate (SM-2-1, 17.22g, 0.11mol), controlling the temperature to be 35-40 ℃ for reaction, adding purified water (500 ml) into reaction liquid after the reaction is detected to be finished, regulating the pH value of an aqueous phase to be 2 by hydrochloric acid, separating liquidThe aqueous phase was further washed with dichloromethane (150 ml × 2), the pH of the aqueous phase was adjusted to 10 with sodium hydroxide solution, dichloromethane (150 ml × 3) was extracted, the organic phase was washed with saturated brine (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to give intermediate I-1-1, yield 93.5%, purity 98.2%.
Example 4
Adding SM-1 (19.13g, 0.10mol) and N, N-diisopropylethylamine (36.19g, 0.28mol) into dichloromethane (100 ml), controlling the temperature to be 5-0 ℃, adding phenyl chloroformate (SM-2-1, 46.97g, 0.30mol), controlling the temperature to be 20-25 ℃ for reaction, after the reaction is detected to be finished, adding purified water (500 ml) into a reaction solution, regulating the pH of an aqueous phase to be 2 by using hydrochloric acid, separating liquid, continuously washing the aqueous phase by using dichloromethane (150 ml multiplied by 2), regulating the pH of the aqueous phase to be 10 by using a sodium hydroxide solution, extracting the dichloromethane (150 ml multiplied by 3), washing an organic phase by using saturated saline water (100 ml multiplied by 2), drying anhydrous sodium sulfate, filtering, concentrating a filtrate under reduced pressure to be dry to obtain an intermediate I-1-1, wherein the yield is 95.8%, and the purity is 97.6%.
Example 5
Adding SM-1 (19.13g, 0.10mol) and pyridine (22.15g, 0.28mol) into dichloromethane (100 ml), controlling the temperature to be 10-0 ℃, adding phenyl chloroformate (SM-2-1, 48.54g, 0.31mol), controlling the temperature to be 15-20 ℃ for reaction, after the detection reaction is finished, adding purified water (500 ml) into a reaction solution, regulating the pH value of an aqueous phase to be 2 by using hydrochloric acid, separating liquid, continuously washing the aqueous phase by using dichloromethane (150 ml multiplied by 2), regulating the pH value of the aqueous phase to be 10 by using a sodium hydroxide solution, extracting methyl tert-butyl ether (150 ml multiplied by 3), washing an organic phase by using saturated saline (100 ml multiplied by 2), drying by anhydrous sodium sulfate, filtering, and concentrating a filtrate under reduced pressure until the filtrate is dry to obtain an intermediate I-1-1, wherein the yield is 95.7% and the purity is 97.5%.
Example 6
Adding SM-1 (19.13g, 0.10mol) and triethylamine (22.260.22mol) into dichloromethane (100 ml), controlling the temperature to be 5-10 ℃, adding p-nitrophenylchloroformate (SM-2-2, 32.25g, 0.11mmol), controlling the temperature to be 30-35 ℃ for reaction, after the detection reaction is finished, adding purified water (500 ml) into a reaction solution, regulating the pH value of an aqueous phase to be 2 by using hydrochloric acid, separating liquid, continuously washing the aqueous phase by using dichloromethane (150 ml multiplied by 2), regulating the pH value of the aqueous phase to be 9 by using a sodium hydroxide solution, extracting dichloromethane (150 ml multiplied by 3), washing an organic phase by using saturated saline (100 ml multiplied by 2), drying by anhydrous sodium sulfate, filtering, and concentrating a filtrate under reduced pressure to be dry to obtain an intermediate I-1-2, wherein the yield is 95.1% and the purity is 98.0%. The reaction route is as follows:
example 7
Adding SM-1 (19.13g, 0.10mol) and triethylamine (21.25g, 0.21mol) into chloroform (100 ml), controlling the temperature to be 5-10 ℃, adding phenyl chloroformate (SM-2-1, 25.05g, 0.11mmol), controlling the temperature to be 30-35 ℃ for reaction, after the detection reaction is finished, adding purified water (500 ml) into a reaction solution, regulating the pH value of an aqueous phase to be 2 by using hydrochloric acid, separating liquid, continuously washing the aqueous phase by using chloroform (150 ml multiplied by 2), regulating the pH value of the aqueous phase by using a sodium hydroxide solution to be 10, extracting chloroform (150 ml multiplied by 3), washing an organic phase by using saturated saline (100 ml multiplied by 2), drying by anhydrous sodium sulfate, filtering, and concentrating a filtrate under reduced pressure until the purity is dry, namely the intermediate I-1-1, wherein the yield is 94.8% and the purity is 97.9%.
Example 8
Adding SM-1 (19.13g, 0.10mol) and triethylamine (50.60g, 0.50mol) into dichloromethane (100 ml), controlling the temperature to be-5-0 ℃, adding phenyl chloroformate (SM-2-1, 25.05g, 0.110mol), controlling the temperature to be 20-25 ℃ for reaction, after the detection reaction is finished, adding purified water (500 ml) into a reaction solution, regulating the pH value of an aqueous phase to be 3 by using hydrochloric acid, separating liquid, continuously washing the aqueous phase by using dichloromethane (150 ml multiplied by 2), regulating the pH value of the aqueous phase to be 10 by using a sodium hydroxide solution, extracting ethyl acetate (150 ml multiplied by 3), washing an organic phase by using saturated saline (100 ml multiplied by 2), drying by anhydrous sodium sulfate, filtering, and concentrating a filtrate under reduced pressure to be dry to obtain an intermediate I-1-1, wherein the purity is 95.6% and 97.8%.
Example 9
Adding SM-1 (19.13g, 0.10mol) and triethylamine (51.610.51mol) into dichloromethane (100 ml), controlling the temperature to be-5-0 ℃, adding phenyl chloroformate (SM-2-1, 25.05g, 0.10mol), controlling the temperature to be 20-25 ℃ for reaction, after the detection reaction is finished, adding purified water (500 ml) into a reaction solution, regulating the pH value of an aqueous phase to be 1 by using hydrochloric acid, separating, continuously washing the aqueous phase by using dichloromethane (150 ml multiplied by 2), regulating the pH value of the aqueous phase to be 10 by using a sodium hydroxide solution, extracting chloroform (150 ml multiplied by 3), washing an organic phase by using saturated saline (100 ml multiplied by 2), drying by anhydrous sodium sulfate, filtering, and concentrating a filtrate under reduced pressure until the filtrate is dried to obtain an intermediate I-1-1, wherein the yield is 95.7% and the purity is 97.5%.
I synthesis:
example 10
Adding the intermediate I-1-1 (15.57g, 0.05mol) and SM-3 (10.15g, 0.06mol) into dichloromethane (120 ml), controlling the temperature to be 30-35 ℃ to finish the reaction, after the detection reaction is finished, concentrating the reaction liquid under reduced pressure to be dry, and passing through a dichloromethane-methanol system (V) Methylene dichloride :V Methanol =3, 1, 50 ml) to obtain the target product I with the yield of 98.7% and the purity of 99.8%. The reaction route is as follows:
example 11
Adding the intermediate I-1-1 (15.57g, 0.05mol) and SM-3 (9.31g, 0.055mol) into dichloromethane (120 ml), controlling the temperature to be 30-35 ℃ to finish the reaction, detecting that the reaction is finished, concentrating the reaction solution under reduced pressure to be dry after the reaction is finished, and performing a dichloromethane-methanol system (V) Methylene dichloride :V Methanol =2, 40 ml) to obtain the target product I, the yield is 97.5%, and the purity is 99.6%.
Example 12
Adding the intermediate I-1-1 (15.57g, 0.05mol) and SM-3 (8.88g, 0.0525mol) into dichloromethane (120 ml), controlling the temperature to be 45-50 ℃ to finish the reaction, detecting that the reaction is finished, concentrating the reaction solution under reduced pressure to be dry, and passing through a dichloromethane-methanol system (V) Methylene dichloride :V Methanol = 4.
Example 13
Adding the intermediate I-1-1 (15.57g, 0.05mol) and SM-3 (12.69g, 0.075 mol) into dichloromethane (120 ml), controlling the temperature to be 25-30 ℃ to finish the reaction, after the detection reaction is finished, concentrating the reaction solution under reduced pressure to be dry, and passing through a dichloromethane-methanol system (V) Methylene dichloride :V Methanol =3, 1, 50 ml) to obtain the target product I with 97.6% of yield and 99.7% of purity.
Example 14
Adding the intermediate I-1-1 (15.57g, 0.05mol) and SM-3 (13.54g, 0.08mol) into dichloromethane (120 ml), controlling the temperature to be 20-25 ℃ to finish the reaction, after the detection reaction is finished, concentrating the reaction solution under reduced pressure to be dry, and passing through a dichloromethane-methanol system (V) Methylene dichloride :V Methanol = 3.
Example 15
Adding the intermediate I-1-2 (17.82g, 0.05mol) and SM-3 (10.15g, 0.06mol) into chloroform (120 ml), controlling the temperature to be 30-35 ℃ to finish the reaction, detecting the reaction, concentrating the reaction liquid under reduced pressure to be dry after the reaction is finished, and performing a dichloromethane-methanol system (V) Methylene dichloride :V Methanol =3, 1, 50 ml) to obtain the target product I with the yield of 98.4% and the purity of 99.7%. The reaction route is as follows:
Claims (10)
1. a preparation method of a lefenacin intermediate is characterized by comprising the following steps: 1-benzyl piperidine-4-alcohol is acylated by SM-2 to prepare an intermediate I-1, the intermediate I-1 is aminolyzed by [1,1 '-biphenyl ] -2-amine to prepare a target compound 1-benzyl piperidine-4-yl [1,1' -biphenyl ] -2-yl carbamate, and the reaction formula is as follows:
wherein RR is H or NO 2 。
2. The preparation method according to claim 1, comprising the following steps:
step 1, adding SM-1 and an acid binding agent into a reaction solvent,temperature control T 1A Adding SM-2, controlling the temperature T 1B After the reaction is finished, carrying out post-treatment to obtain an intermediate I-1;
and 2, adding the intermediates I-1 and SM-3 into a reaction solvent, controlling the temperature until the reaction is finished, and carrying out post-treatment to obtain the target compound I.
3. The method according to claim 1 or 2, wherein SM-2 in step 1 is one of phenyl chloroformate or p-nitrophenyl chloroformate.
4. The method according to claim 2, wherein the acid-binding agent in step 1 is K 2 CO 3 、Na 2 CO 3 One or the combination of triethylamine, N-diisopropylethylamine and pyridine.
5. The method according to claim 2, wherein the reaction solvent in step 1 and step 2 is one of dichloromethane, chloroform, or a combination thereof.
6. The preparation method according to claim 2, wherein the feeding molar ratio of the SM-1 to the SM-2 to the acid-binding agent in step 1 is 1.2-3.0: 2.2 to 5.0; t described in step 1 1A Is-10 to 10 ℃, preferably 0 to 5 ℃; reaction temperature T 1B Is 15 to 40 ℃, preferably 25 to 30 ℃.
7. The preparation method according to claim 2, wherein the feeding molar ratio of I-1 to SM-3 in step 2 is 1; the reaction temperature in step 2 is 20 to 50 ℃, preferably 30 to 35 ℃.
8. The method according to claim 2, wherein the post-treatment step in step 1 is: adding purified water into the reaction solution, regulating the pH value of the water phase to 1-3 by hydrochloric acid, separating liquid, continuously washing the water phase by dichloromethane, regulating the pH value of the water phase to 9-10 by sodium hydroxide solution, extracting by an organic solvent, washing the organic phase by saturated saline solution, drying, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dried to obtain the intermediate I-1.
9. The method of claim 8, wherein the extraction solvent includes but is not limited to one or a combination of dichloromethane, chloroform, ethyl acetate, methyl tert-butyl ether.
10. The method according to claim 2, wherein the post-treatment step of step 2 is as follows: after the reaction is finished, concentrating the reaction solution under reduced pressure to be dry, and recrystallizing by a dichloromethane-methanol system to obtain a target product I.
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