CN117105958A - Method for preparing 5-HT3 receptor modulators - Google Patents
Method for preparing 5-HT3 receptor modulators Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 29
- 102000035037 5-HT3 receptors Human genes 0.000 title 1
- 108091005477 5-HT3 receptors Proteins 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 94
- 150000001875 compounds Chemical class 0.000 claims description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 230000035484 reaction time Effects 0.000 claims description 32
- 239000003960 organic solvent Substances 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 20
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 18
- -1 sodium triacetoxyborohydride Chemical group 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- 238000000746 purification Methods 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- 239000012074 organic phase Substances 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 229940126214 compound 3 Drugs 0.000 claims description 12
- 229940125898 compound 5 Drugs 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 239000003208 petroleum Substances 0.000 claims description 11
- 229940125773 compound 10 Drugs 0.000 claims description 10
- 229940125782 compound 2 Drugs 0.000 claims description 10
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical group COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 claims description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical group BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 239000012024 dehydrating agents Substances 0.000 claims description 8
- 239000005457 ice water Substances 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 7
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical group COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 229940125904 compound 1 Drugs 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 230000031709 bromination Effects 0.000 claims description 4
- 238000005893 bromination reaction Methods 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical group CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 claims description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 claims description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 239000012065 filter cake Substances 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 2
- 239000003223 protective agent Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 230000002140 halogenating effect Effects 0.000 claims 1
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 abstract description 20
- 239000003814 drug Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 229940075993 receptor modulator Drugs 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- GFOGPMFLGWHHJF-UHFFFAOYSA-N indazol-6-one Chemical compound O=C1C=CC2=CN=NC2=C1 GFOGPMFLGWHHJF-UHFFFAOYSA-N 0.000 description 11
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 9
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 208000002551 irritable bowel syndrome Diseases 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- YRCSUTRLSRFUKC-UHFFFAOYSA-N methyl 3-bromo-2h-indazole-4-carboxylate Chemical compound COC(=O)C1=CC=CC2=NNC(Br)=C12 YRCSUTRLSRFUKC-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010000060 Abdominal distension Diseases 0.000 description 1
- 206010007270 Carcinoid syndrome Diseases 0.000 description 1
- 208000031649 Postoperative Nausea and Vomiting Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 208000024330 bloating Diseases 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- SNQXJPARXFUULZ-UHFFFAOYSA-N dioxolane Chemical compound C1COOC1 SNQXJPARXFUULZ-UHFFFAOYSA-N 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000007160 gastrointestinal dysfunction Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- MEXWKIOTIDFYPN-UHFFFAOYSA-N methyl 1h-indazole-4-carboxylate Chemical compound COC(=O)C1=CC=CC2=C1C=NN2 MEXWKIOTIDFYPN-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention provides a method for preparing 5-HT 3 A method for preparing receptor modulator, belonging to the field of drug synthesis. The 5-HT 3 The structure of the receptor modulator is shown as a formula I. The synthesis method has the advantages of easily obtained raw materials, mild reaction conditions, high total yield up to 45.1 percent and high product purity up to 97 percent, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a method for preparing 5-HT 3 Methods of receptor modulators.
Background
Irritable bowel syndrome (irritable bowel syndrome, IBS) is a continuous or intermittent episode of intestinal dysfunction disease with changes in abdominal pain, bloating, bowel habits and/or stool traits into clinical manifestations, lacking gastrointestinal structure and biochemical abnormalities. Roman III classifies the disease as a functional bowel disease, the disease onset age is usually 20-50 years old, women are more common than men, and family aggregation tendency is usually accompanied with other gastrointestinal dysfunction diseases such as functional dyspepsia. The prevalence of irritable bowel syndrome in adults is 10% -20%, and few drugs currently available for the effective treatment of this disease are available.
Research has shown that 5-hydroxytryptamine (5-HT) is one of the key neurotransmitters in the gastrointestinal tract, 5-hydroxytryptamine 3 (5-HT) 3 ) The receptor is an important target for developing medicines for treating irritable bowel syndrome, carcinoid syndrome and emesis. Example 23 of chinese patent with publication No. CN102046176B discloses a compound and a method for preparing the same: (S) -7- (quinin-3-yl) -2,7,8,9-tetrahydro-6H-azacyclo [5,4,3-cd ]]Indazol-6-ones (structures shown below) which are useful as 5-HT 3 The receptor modulator can be used for treating various diseases such as nausea and vomiting, postoperative nausea and vomiting, irritable bowel syndrome and the like caused by chemotherapy, and has wide application prospect. However, the preparation of (S) -7- (quinin-3-yl) -2,7,8,9-tetrahydro-6H-azacyclo [5,4,3-cd ]]The indazole-6-ketone method has high cost, the total yield is as low as below 10 percent, and the method is not suitable for large-scale popularization.
It is important to develop a method for synthesizing (S) -7- (quinine-3-yl) -2,7,8,9-tetrahydro-6H-azacyclo [5,4,3-cd ] indazol-6-one with higher yield.
Disclosure of Invention
The object of the present invention is to provide a novel process for the preparation of (S) -7- (quinin-3-yl) -2,7,8,9-tetrahydro-6H-azacyclo [5,4,3-cd ] indazol-6-one.
The invention provides a method for synthesizing a compound shown in a formula I, which comprises the following steps:
(1) Reacting the compound 5 with an acid to obtain a compound 6;
(2) Reacting compound 6 with compound 7 or a salt thereof to give compound 8;
(3) Reacting the compound 8 with lithium hydroxide or a hydrate thereof to obtain a compound 9;
(4) Reacting the compound 9 in the presence of a base and a dehydrating agent to obtain a compound 10;
(5) Reacting the compound 10 with a deprotection reagent to obtain a compound shown in a formula I;
R 1 is an amino protecting group.
Further, in the step (1), the acid is hydrochloric acid, the molar ratio of the compound 5 to the acid is 1 (5-20), the solvent for the reaction is an organic solvent, the reaction temperature is 40-60 ℃, and the reaction time is 2-6 hours;
in the step (2), the reaction is carried out in the presence of an acid and a reducing agent, wherein the molar ratio of the compound 6, the compound 7 or the salt thereof, the acid and the reducing agent is 1: (1-4): (1-4): (1-4), wherein the solvent for the reaction is an organic solvent, the reaction temperature is 20-40 ℃, and the reaction time is 12-22 hours;
in the step (3), the molar ratio of the compound 8 to the lithium hydroxide or the hydrate thereof is 1, (1-4), the solvent for the reaction is one or a mixture of two of water and an organic solvent, the reaction temperature is 50-90 ℃, and the reaction time is 0.5-3 hours;
in the step (4), the mass ratio of the compound 9 to the alkali is 1 (1-3), the molar ratio of the alkali to the dehydrating agent is 1 (1-3), the alkali is an organic alkali, the dehydrating agent is 1-propyl phosphoric anhydride, the solvent for the reaction is an organic solvent, the reaction temperature is 20-40 ℃, and the reaction time is 6-20 hours;
in the step (5), the deprotection reagent is trifluoroacetic acid, the mass volume ratio of the compound 10 to the trifluoroacetic acid is 50-70mg/mL, the solvent for reaction is an organic solvent, the reaction temperature is 60-100 ℃, and the reaction time is 6-20 hours.
Further, in the step (1), the concentration of the hydrochloric acid is 5-7mol/L, the molar ratio of the compound 5 to the acid is 1:12, the organic solvent is tetrahydrofuran, the reaction temperature is 50 ℃, and the reaction time is 4 hours;
in the step (2), the reducing agent is sodium triacetoxyborohydride, the salt of the compound 7 is dihydrochloride of the compound 7, the mol ratio of the compound 6 to the compound 7 or the salt, the acid and the reducing agent is 1:2:1:2, the organic solvent is acetonitrile, the reaction temperature is room temperature, and the reaction time is 16-18 hours;
in the step (3), the molar ratio of the compound 8 to the lithium hydroxide or the hydrate thereof is 1:2, the lithium hydroxide hydrate is lithium hydroxide monohydrate, the solvent for the reaction is one or a mixture of methanol and water, the temperature of the reaction is 70 ℃, and the reaction time is 1 hour;
in the step (4), the mass ratio of the compound 9 to the alkali is 1:1.5, the molar ratio of the alkali to the dehydrating agent is 1.6:1, the organic alkali is N, N-diisopropylethylamine, the organic solvent is one or a mixture of tetrahydrofuran and ethyl acetate, the reaction temperature is room temperature, and the reaction time is 8-12 hours;
in the step (5), the mass-volume ratio of the compound 10 to the trifluoroacetic acid is 62.5mg/mL, the organic solvent is anisole, the reaction temperature is 80 ℃, and the reaction time is 8-12 hours.
Further, in the step (1), after the reaction is finished, the method further comprises the following purification steps: adding the reaction solution into ice water, regulating the pH to 9-11 with saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate, retaining an organic phase, and drying to obtain a compound 6;
in the step (2), the reaction further comprises the following purification steps: adding the reaction solution into ice water, extracting with dichloromethane, adjusting the pH of the water phase to 9-11 with saturated sodium bicarbonate aqueous solution, extracting with dichloromethane, retaining an organic phase, and drying to obtain a compound 8;
in the step (4), the reaction further comprises the following purification steps: adding the reaction solution into water, extracting with dichloromethane, reserving an organic phase, and drying to obtain a compound 10;
in the step (5), the reaction further comprises the following purification steps: adding hydrochloric acid into the reaction liquid, extracting with methyl tertiary butyl ether, regulating the pH of the aqueous phase to 9-11, extracting with dichloromethane solution, retaining organic phase, and drying to obtain the compound shown in formula I.
Further, the preparation method of the compound 5 comprises the following steps: reacting the compound 3 with a compound 4 to obtain a compound 5;
R 1 is an amino protecting group and X is halogen.
Further, the reaction is carried out in the presence of a palladium catalyst and a phase transfer catalyst, and the molar ratio of the compound 3, the compound 4, the palladium catalyst and the phase transfer catalyst is 1: (1-3): (0.01-0.1): (1-3), the solvent for the reaction is one or a mixture of water and an organic solvent, the reaction temperature is 40-60 ℃, and the reaction time is 12-20h.
Further, the palladium catalyst is dichloro di-tert-butyl- (4-dimethylaminophenyl) palladium (II), the phase transfer catalyst is cesium carbonate, and the molar ratio of the compound 3 to the compound 4 to the palladium catalyst to the phase transfer catalyst is 1:1.5:0.05:2, the solvent for reaction is one or two of water and 1, 4-dioxane, the reaction temperature is 50 ℃, and the reaction time is 16 hours;
preferably, the reaction further comprises the following purification steps after completion: concentrating the reaction solution, and performing column chromatography to obtain a compound 5; the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 6:1.
Further, the preparation method of the compound 3 comprises the following steps:
(a) Reacting the compound 1 with a halogenated reagent to obtain a compound 2;
(b) Reacting the compound 2 with an amino protective agent to obtain a compound 3;
x is halogen, R 1 Is an amino protecting group.
Further, in step (a), the halogenated reagent is a brominating reagent, and the reaction is performed in the presence of a base; the mol ratio of the compound 1 to the bromination reagent to the alkali is 1 (0.8-1.2) (2-6), the reaction solvent is an organic solvent, the reaction temperature is 20-40 ℃, and the reaction time is 0.5-3 hours;
in the step (b), the amino protecting reagent is p-methoxybenzyl chloride, the mass volume ratio of the compound 2 to the p-methoxybenzyl chloride is 0.1-0.5g/mL, the reaction temperature is 40-60 ℃, and the reaction time is 5-9 hours;
x is bromine, R 1 Is p-methoxybenzyl.
Further, in step (a), the brominating reagent is N-bromosuccinimide, and the base is an inorganic base, preferably potassium hydroxide; the molar ratio of the compound 1 to the bromination reagent to the alkali is 1:1:4, the organic solvent is N, N-dimethylformamide, the reaction temperature is room temperature, and the reaction time is 1 hour;
preferably, after the reaction of step (a) is completed, the following purification steps are further included: concentrating and filtering the reaction solution, adding the filtrate into ice water, extracting with ethyl acetate, washing the remaining organic phase with saturated saline water, and drying to obtain a compound 2;
in the step (b), the mass-volume ratio of the compound 2 to the p-methoxybenzyl chloride is 0.2g/mL, the reaction temperature is 50 ℃, and the reaction time is 7 hours;
preferably, the reaction of step (b) is completed with the following purification steps: and adding petroleum ether into the reaction solution, stirring, filtering, washing a filter cake with petroleum ether, and drying to obtain the compound 3.
In the present invention, room temperature means 25.+ -. 5 ℃.
The present invention provides a novel process for the preparation of (S) -7- (quinin-3-yl) -2,7,8,9-tetrahydro-6H-azacyclo [5,4,3-cd ] indazol-6-one. The method has the advantages of easily obtained raw materials, mild reaction conditions, high total yield up to 45.1 percent and high product purity up to 97 percent, and is suitable for industrial production.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
Fig. 1: nuclear magnetic spectrum of (S) -7- (quinin-3-yl) -2,7,8,9-tetrahydro-6H-azacyclo [5,4,3-cd ] indazol-6-one obtained in example 1.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
Example 1 preparation of (S) -7- (quinin-3-yl) -2,7,8,9-tetrahydro-6H-azacyclo [5,4,3-cd ] indazol-6-one
The first step: preparation of 3-bromo-1H-indazole-4-carboxylic acid methyl ester
1H-indazole-4-carboxylic acid methyl ester (45.0 g,255.6 mmol) was dissolved in dry N, N-dimethylformamide (0.9L), potassium hydroxide (57.0 g,1022.7 mmol) was added, N-bromosuccinimide (abbreviated as NBS,45.5g,255.7 mmol) was added in portions to the reaction system with stirring, and reacted at room temperature for 1H. After the completion of the reaction, residual potassium hydroxide was removed by filtration under reduced pressure, the filtrate was poured into 3L of ice water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 3-bromo-1H-indazole-4-carboxylate (59.8 g, yield 92.4%) as a yellow solid.
MS m/z(ESI):255.0,257.0[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.80(dd,J＝8.5,0.7Hz,1H),7.69(dd,J＝7.2,0.7Hz,1H),7.49(dd,J＝8.5,7.2Hz,1H),4.04(s,3H).
And a second step of: preparation of 3-bromo-2- (4-methoxybenzyl) -2H-indazole-4-carboxylic acid methyl ester hydrochloride
3-bromo-1H-indazole-4-carboxylic acid methyl ester (30.0 g,117.6 mmol) was added to p-methoxybenzyl chloride (PMB-Cl for short, 150 mL) and reacted at 50℃for 7H. After the reaction was completed, the reaction mixture was cooled to room temperature, the system was added to 1L of petroleum ether, stirred for 1H, filtered under reduced pressure, and the cake was washed with 0.4L of petroleum ether, and dried to give 3-bromo-2- (4-methoxybenzyl) -2H-indazole-4-carboxylic acid methyl ester hydrochloride as a white solid (39.7 g, yield 82%).
MS m/z(ESI):374.0,376.0[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.88(dd,J＝8.9,0.8Hz,1H),7.77–7.59(dd,J＝8.9,0.8Hz,1H),7.37–7.16(m,3H),6.90–6.64(m,2H),5.66(d,J＝24.0Hz,2H),3.97(s,3H),3.77(s,3H).
And a third step of: preparation of methyl (E) -3- (2-ethoxyvinyl) -2- (4-methoxybenzyl) -2H-indazole-4-carboxylate
3-bromo-2- (4-methoxybenzyl) -2H-indazole-4-carboxylic acid methyl ester hydrochloride (5.5 g,13.3 mmol), (E) -2- (2-ethoxyvinyl) -4, 5-tetramethyl-1, 3, 2-dioxolane (4.0 g,20.0 mmol), bis-tert-butyl (4-dimethylaminophenyl) palladium (II) dichloride (0.5 g,0.7 mmol), cesium carbonate (Cs for short 2 CO 3 8.6g,26.6 mmol), 1, 4-dioxane (55 mL), water (11 mL) were mixed in a 100mL single-necked flask and reacted at 50℃for 16h. After the reaction was completed, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and then subjected to column chromatography on silica gel (eluent: petroleum ether/ethyl acetate volume ratio=6/1)), to give methyl (E) -3- (2-ethoxyvinyl) -2- (4-methoxybenzyl) -2H-indazole-4-carboxylate (4.00 g, yield 82.0%) as a white solid.
MS m/z(ESI):367.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.87(dd,J＝8.6,0.7Hz,1H),7.65(dd,J＝6.9,0.7Hz,1H),7.27(dd,J＝6.9,8.3Hz,1H),7.14–7.12(m,2H),6.94–6.66(m,2H),6.42(d,J＝13.2Hz,1H),6.12(d,J＝13.2Hz,1H),5.62(s,2H),3.93(q,7.0Hz,2H),3.93–3.88(s,3H),3.77(s,3H),1.36(t,J＝7.0Hz,3H).
Fourth step: preparation of methyl 2- (4-methoxybenzyl) -3- (2-oxoethyl) -2H-indazole-4-carboxylate
Methyl (E) -3- (2-ethoxyvinyl) -2- (4-methoxybenzyl) -2H-indazole-4-carboxylate (3.7 g,10.1 mmol), tetrahydrofuran (40 mL), and hydrochloric acid (20 mL, 6N) were added to a 100mL single bottle and reacted at 50℃for 4H. After the reaction was cooled to room temperature, the system was poured into ice water, ph=8 was adjusted with saturated aqueous sodium bicarbonate, extraction was performed three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give methyl 2- (4-methoxybenzyl) -3- (2-oxoethyl) -2H-indazole-4-carboxylate (3.1 g, yield 90.6%) as a white solid.
MS m/z(ESI):339.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ9.58(s,1H),7.92(dd,J＝8.6,0.8Hz,1H),7.72(dd,J＝8.6,0.8Hz,1H),7.34(dd,J＝8.6,7.1Hz,1H),7.17–7.15(m,2H),6.98–6.66(m,2H),5.62(s,2H),4.53(s,2H),3.79(s,3H),3.71(s,3H).
Fifth step: preparation of methyl (S) -2- (4-methoxybenzyl) -3- (2- (quinin-3-ylamino) ethyl) -2H-indazole-4-carboxylate
To a solution of 2- (4-methoxybenzyl) -3- (2-oxoethyl) -2H-indazole-4-carboxylic acid methyl ester (310.0 mg,0.92 mmol) and S-3-aminoquinuclidine dihydrochloride (360.0 mg,1.84 mmol) in acetonitrile (6 mL) was added glacial acetic acid (60.0 mg,1 mmol), and the mixture was stirred at room temperature for 16 hours. Then, sodium triacetoxyborohydride (390.0 mg,1.84 mmol) was added to the reaction solution, and the mixture was stirred at room temperature. After the completion of the reaction, the reaction mixture was poured into water, extracted once with dichloromethane, the aqueous phase was adjusted to ph=8 with saturated aqueous sodium bicarbonate, extracted twice with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl (S) -2- (4-methoxybenzyl) -3- (2- (quinin-3-ylamino) ethyl) -2H-indazole-4-carboxylate (374.0 mg, yield 91.4%) as an oil.
MS m/z(ESI):449.2[M+H] +
Sixth step: preparation of lithium (S) -2- (4-methoxybenzyl) -3- (2- (quinin-3-ylamino) ethyl) -2H-indazole-4-carboxylate
To a solution of methyl (S) -2- (4-methoxybenzyl) -3- (2- (quinin-3-ylamino) ethyl) -2H-indazole-4-carboxylate (310.0 mg,0.7 mmol) in methanol (5 mL) was added a solution of lithium hydroxide monohydrate (58.0 mg,1.4 mmol) in water (1 mL) and reacted at 70℃for 1H. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to give lithium (S) -2- (4-methoxybenzyl) -3- (2- (quinin-3-ylamino) ethyl) -2H-indazole-4-carboxylate (crude product), which was used in the next step without further purification.
MS m/z(ESI):435.2[M+H] + .
Seventh step: preparation of (S) -2- (4-methoxybenzyl) -7- (quinin-3-yl) -2,7,8,9-tetrahydro-6H-azacyclo [5,4,3-cd ] indazol-6-one
To a solution of lithium (S) -2- (4-methoxybenzyl) -3- (2- (quinin-3-ylamino) ethyl) -2H-indazole-4-carboxylate (320.0 mg, crude) and N, N-diisopropylethylamine (DIEA, for short, 469.0mg,3.6 mmol) in tetrahydrofuran (6 mL) was added 1-propylphosphoric anhydride (50 wt% strength in ethyl acetate) (T for short) 3 P,1.4g,2.2 mmol) was stirred overnight at room temperature. After the completion of the reaction, the reaction mixture was poured into water and extracted twice with a dichloromethane solution. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (S) -2- (4-methoxybenzyl) -7- (quinin-3-yl) -2,7,8,9-tetrahydro-6H-azacyclo [5,4,3-cd ]]Indazol-6-one (250.0 mg, crude) was used directly in the next step without further purification.
MS m/z(ESI):417.2[M+H] + .
Eighth step: preparation of (S) -7- (quinin-3-yl) -2,7,8,9-tetrahydro-6H-azacyclo [5,4,3-cd ] indazol-6-one
The compound (S) -2- (4-methoxybenzyl) -7- (quinin-3-yl) -2,7,8,9-tetrahydro-6H-azacyclo [5,4,3-cd ] indazol-6-one (250 mg, crude), trifluoroacetic acid (4 mL), anisole (1 mL) was mixed and heated to 80 ℃ for reaction overnight. After the reaction was cooled to room temperature, 50mL of hydrochloric acid (1M) was added, extraction was performed twice with methyl tert-butyl ether, the aqueous phase was adjusted to ph=10 with aqueous sodium hydroxide (6M), and extraction was performed twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S) -7- (quinin-3-yl) -2,7,8,9-tetrahydro-6H-azacyclo [5,4,3-cd ] indazol-6-one (156.0 mg, 87.6% yield, 97% HPLC purity).
MS m/z(ESI):297.2[M+H] + .
1 H NMR(400MHz,DMSO)δ7.45(d,J＝8.1Hz,1H),7.27(d,J＝6.9Hz,1H),6.80(dd,J＝8.0,7.2Hz,1H),4.52–4.28(m,1H),4.16–3.88(m,1H),3.71–3.47(m,1H),3.33–2.87(m,5H),2.84–2.65(m,3H),2.06–1.87(m,1H),1.81–1.49(m,3H),1.50–1.30(m,1H).
The overall yield of (S) -7- (quinin-3-yl) -2,7,8,9-tetrahydro-6H-azacyclo [5,4,3-cd ] indazol-6-one prepared in example 1 of the present invention is as high as 45.1%.
In summary, the present invention provides a method for preparing the 5-HT of formula I 3 Methods of receptor modulators. The synthesis method has the advantages of easily obtained raw materials, mild reaction conditions, high total yield up to 45.1 percent and high product purity up to 97 percent, and is suitable for industrial production.
Claims (10)
1. A method of synthesizing a compound of formula I, characterized by: the method comprises the following steps:
(1) Reacting the compound 5 with an acid to obtain a compound 6;
(2) Reacting compound 6 with compound 7 or a salt thereof to give compound 8;
(3) Reacting the compound 8 with lithium hydroxide or a hydrate thereof to obtain a compound 9;
(4) Reacting the compound 9 in the presence of a base and a dehydrating agent to obtain a compound 10;
(5) Reacting the compound 10 with a deprotection reagent to obtain a compound shown in a formula I;
R 1 is an amino protecting group.
2. The method according to claim 1, characterized in that: in the step (1), the acid is hydrochloric acid, the molar ratio of the compound 5 to the acid is 1 (5-20), the solvent for the reaction is an organic solvent, the reaction temperature is 40-60 ℃, and the reaction time is 2-6 hours;
in the step (2), the reaction is carried out in the presence of an acid and a reducing agent, wherein the molar ratio of the compound 6, the compound 7 or the salt thereof, the acid and the reducing agent is 1: (1-4): (1-4): (1-4), wherein the solvent for the reaction is an organic solvent, the reaction temperature is 20-40 ℃, and the reaction time is 12-22 hours;
in the step (3), the molar ratio of the compound 8 to the lithium hydroxide or the hydrate thereof is 1, (1-4), the solvent for the reaction is one or a mixture of two of water and an organic solvent, the reaction temperature is 50-90 ℃, and the reaction time is 0.5-3 hours;
in the step (4), the mass ratio of the compound 9 to the alkali is 1 (1-3), the molar ratio of the alkali to the dehydrating agent is 1 (1-3), the alkali is an organic alkali, the dehydrating agent is 1-propyl phosphoric anhydride, the solvent for the reaction is an organic solvent, the reaction temperature is 20-40 ℃, and the reaction time is 6-20 hours;
in the step (5), the deprotection reagent is trifluoroacetic acid, the mass volume ratio of the compound 10 to the trifluoroacetic acid is 50-70mg/mL, the solvent for reaction is an organic solvent, the reaction temperature is 60-100 ℃, and the reaction time is 6-20 hours.
3. The method according to claim 2, characterized in that: in the step (1), the concentration of the hydrochloric acid is 5-7mol/L, the molar ratio of the compound 5 to the acid is 1:12, the organic solvent is tetrahydrofuran, the reaction temperature is 50 ℃, and the reaction time is 4 hours;
in the step (2), the reducing agent is sodium triacetoxyborohydride, the salt of the compound 7 is dihydrochloride of the compound 7, the mol ratio of the compound 6 to the compound 7 or the salt, the acid and the reducing agent is 1:2:1:2, the organic solvent is acetonitrile, the reaction temperature is room temperature, and the reaction time is 16-18 hours;
in the step (3), the molar ratio of the compound 8 to the lithium hydroxide or the hydrate thereof is 1:2, the lithium hydroxide hydrate is lithium hydroxide monohydrate, the solvent for the reaction is one or a mixture of methanol and water, the temperature of the reaction is 70 ℃, and the reaction time is 1 hour;
in the step (4), the mass ratio of the compound 9 to the alkali is 1:1.5, the molar ratio of the alkali to the dehydrating agent is 1.6:1, the organic alkali is N, N-diisopropylethylamine, the organic solvent is one or a mixture of tetrahydrofuran and ethyl acetate, the reaction temperature is room temperature, and the reaction time is 8-12 hours;
in the step (5), the mass-volume ratio of the compound 10 to the trifluoroacetic acid is 62.5mg/mL, the organic solvent is anisole, the reaction temperature is 80 ℃, and the reaction time is 8-12 hours.
4. A method according to claim 3, characterized in that: in the step (1), the reaction further comprises the following purification steps: adding the reaction solution into ice water, regulating the pH to 9-11 with saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate, retaining an organic phase, and drying to obtain a compound 6;
in the step (2), the reaction further comprises the following purification steps: adding the reaction solution into ice water, extracting with dichloromethane, adjusting the pH of the water phase to 9-11 with saturated sodium bicarbonate aqueous solution, extracting with dichloromethane, retaining an organic phase, and drying to obtain a compound 8;
in the step (4), the reaction further comprises the following purification steps: adding the reaction solution into water, extracting with dichloromethane, reserving an organic phase, and drying to obtain a compound 10;
in the step (5), the reaction further comprises the following purification steps: adding hydrochloric acid into the reaction liquid, extracting with methyl tertiary butyl ether, regulating the pH of the aqueous phase to 9-11, extracting with dichloromethane solution, retaining organic phase, and drying to obtain the compound shown in formula I.
5. The method according to any one of claims 1-4, wherein: the preparation method of the compound 5 comprises the following steps: reacting the compound 3 with a compound 4 to obtain a compound 5;
R 1 is an amino protecting group and X is halogen.
6. The method according to claim 5, wherein: the reaction is carried out in the presence of a palladium catalyst and a phase transfer catalyst, and the molar ratio of the compound 3 to the compound 4 to the palladium catalyst to the phase transfer catalyst is 1: (1-3): (0.01-0.1): (1-3), the solvent for the reaction is one or a mixture of water and an organic solvent, the reaction temperature is 40-60 ℃, and the reaction time is 12-20h.
7. The method according to claim 6, wherein: the palladium catalyst is dichloro di-tert-butyl- (4-dimethylaminophenyl) palladium (II), the phase transfer catalyst is cesium carbonate, and the molar ratio of the compound 3 to the compound 4 to the palladium catalyst to the phase transfer catalyst is 1:1.5:0.05:2, the solvent for reaction is one or two of water and 1, 4-dioxane, the reaction temperature is 50 ℃, and the reaction time is 16 hours;
preferably, the reaction further comprises the following purification steps after completion: concentrating the reaction solution, and performing column chromatography to obtain a compound 5; the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 6:1.
8. The method according to any one of claims 5-7, wherein: the preparation method of the compound 3 comprises the following steps:
(a) Reacting the compound 1 with a halogenated reagent to obtain a compound 2;
(b) Reacting the compound 2 with an amino protective agent to obtain a compound 3;
x is halogen, R 1 Is an amino protecting group.
9. The method according to claim 8, wherein: in step (a), the halogenating agent is a brominating agent, and the reaction is carried out in the presence of a base; the mol ratio of the compound 1 to the bromination reagent to the alkali is 1 (0.8-1.2) (2-6), the reaction solvent is an organic solvent, the reaction temperature is 20-40 ℃, and the reaction time is 0.5-3 hours;
in the step (b), the amino protecting reagent is p-methoxybenzyl chloride, the mass volume ratio of the compound 2 to the p-methoxybenzyl chloride is 0.1-0.5g/mL, the reaction temperature is 40-60 ℃, and the reaction time is 5-9 hours;
x is bromine, R 1 Is p-methoxybenzyl.
10. The method according to claim 9, wherein: in step (a), the brominating reagent is N-bromosuccinimide, and the base is an inorganic base, preferably potassium hydroxide; the molar ratio of the compound 1 to the bromination reagent to the alkali is 1:1:4, the organic solvent is N, N-dimethylformamide, the reaction temperature is room temperature, and the reaction time is 1 hour;
preferably, after the reaction of step (a) is completed, the following purification steps are further included: concentrating and filtering the reaction solution, adding the filtrate into ice water, extracting with ethyl acetate, washing the remaining organic phase with saturated saline water, and drying to obtain a compound 2;
in the step (b), the mass-volume ratio of the compound 2 to the p-methoxybenzyl chloride is 0.2g/mL, the reaction temperature is 50 ℃, and the reaction time is 7 hours;
preferably, the reaction of step (b) is completed with the following purification steps: and adding petroleum ether into the reaction solution, stirring, filtering, washing a filter cake with petroleum ether, and drying to obtain the compound 3.
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