CN118206580A - Preparation method of ozagrel hydrochloride intermediate - Google Patents
Preparation method of ozagrel hydrochloride intermediate Download PDFInfo
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- CN118206580A CN118206580A CN202211628777.3A CN202211628777A CN118206580A CN 118206580 A CN118206580 A CN 118206580A CN 202211628777 A CN202211628777 A CN 202211628777A CN 118206580 A CN118206580 A CN 118206580A
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- tert
- dihydro
- ethyl
- butyldimethylsilyloxy
- indene
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- SHZKQBHERIJWAO-AATRIKPKSA-N ozagrel Chemical compound C1=CC(/C=C/C(=O)O)=CC=C1CN1C=NC=C1 SHZKQBHERIJWAO-AATRIKPKSA-N 0.000 title claims abstract description 14
- 229950003837 ozagrel Drugs 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 claims abstract description 23
- YWQGRJZLCDDIDE-UHFFFAOYSA-N 5-formyl-2-propan-2-yloxybenzonitrile Chemical compound CC(C)OC1=CC=C(C=O)C=C1C#N YWQGRJZLCDDIDE-UHFFFAOYSA-N 0.000 claims abstract description 20
- GGQSSXUVEDANNG-NDEPHWFRSA-N tert-butyl n-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-n-[(1s)-4-[5-(3-cyano-4-propan-2-yloxyphenyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1h-inden-1-yl]carbamate Chemical compound C1=C(C#N)C(OC(C)C)=CC=C1C1=NC(C=2C=3CC[C@@H](C=3C=CC=2)N(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)=NO1 GGQSSXUVEDANNG-NDEPHWFRSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000012074 organic phase Substances 0.000 claims description 19
- 239000008213 purified water Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 238000001514 detection method Methods 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 8
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 4
- -1 tert-butyl (S) -2- (tert-butyldimethylsilyloxy) ethyl Chemical group 0.000 claims description 4
- YKLSSMFSVFVQFT-FQEVSTJZSA-N tert-butyl N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-N-[(1S)-4-cyano-2,3-dihydro-1H-inden-1-yl]carbamate Chemical compound C1=CC=C(C#N)C2=C1[C@@H](N(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)CC2 YKLSSMFSVFVQFT-FQEVSTJZSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 abstract description 2
- 150000001263 acyl chlorides Chemical class 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- XRVDGNKRPOAQTN-FQEVSTJZSA-N 5-[3-[(1s)-1-(2-hydroxyethylamino)-2,3-dihydro-1h-inden-4-yl]-1,2,4-oxadiazol-5-yl]-2-propan-2-yloxybenzonitrile Chemical compound C1=C(C#N)C(OC(C)C)=CC=C1C1=NC(C=2C=3CC[C@@H](C=3C=CC=2)NCCO)=NO1 XRVDGNKRPOAQTN-FQEVSTJZSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical group C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 1
- 101150015280 Cel gene Proteins 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 229940121846 Sphingosine 1-phosphate receptor agonist Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229950008141 ozanimod Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicine synthesis, and provides a preparation method of an ozagrel intermediate, wherein the method is characterized in that a compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 reacts with 5-formyl-2-isopropoxybenzonitrile SM to prepare a compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazole-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I; the preparation method provided by the invention avoids side reactions caused by selecting acid or acyl chloride and other substrates in the prior art. Improves the reaction yield and purity, and is 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 an ozagrel hydrochloride intermediate.
Background
Ozagrel, english name Ozanimod, chemical name 5- [3- [ (1S) -2, 3-dihydro-1- [ (2-hydroxyethyl) amino ] -1H-inden-4-yl ] -1,2, 4-oxadiazol-5-yl ] -2- (1-methylethoxy) -benzonitrile. Ozagru is a sphingosine 1 phosphate receptor agonist for treating Multiple Sclerosis (MS) and ulcerative colitis, which is developed in combination by the united states Scripps institute and Celgene company, and is mainly used for treating multiple sclerosis, ulcerative colitis and crohn's disease, and has the chemical structural formula as follows:
There are many documents reported about the synthesis of ozagrel hydrochloride, among which, the synthesis routes in U.S. Pat. No.3,327A 1 (WO 2016164180), CN102762100B (WO 2011060392), US20210340115A1 are as follows:
However, this process has the following problems in the preparation of the key intermediate (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-inden-1-yl) carbamic acid tert-butyl ester I during the cyclization process: ① The condensing agent HOBt/EDC is needed to participate, on one hand, the byproducts are difficult to remove, and on the other hand, the atom economy is low; ② The reaction was required to be carried out overnight at 85℃and was likewise of low purity, only 67%.
In view of the above-described deficiencies in the current preparation of the key intermediate (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-inden-1-yl) carbamic acid tert-butyl ester I of ozagrel hydrochloride. Therefore, the research and search of a process for preparing the (S) -2- (tert-butyldimethylsilyloxy) ethyl (tert-butyl 4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamate I which is a key intermediate of ozagrel hydrochloride, has mild reaction conditions, simple operation process, high product yield and high purity, and is suitable for industrial production still needs to be solved.
Disclosure of Invention
Aiming at a plurality of problems existing in the prior preparation of the ozagrel hydrochloride key intermediate (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-inden-1-yl) carbamic acid tert-butyl ester I, the invention provides a novel preparation method of the ozagrel hydrochloride key intermediate (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-inden-1-yl) carbamic acid tert-butyl ester I. The method has mild reaction conditions, safe and simple operation process, and the prepared target product has higher purity and yield.
The specific technical scheme of the invention is as follows:
A preparation method of an ozagrel hydrochloride key intermediate I shown in a formula (I) comprises the steps of reacting a compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 with 5-formyl-2-isopropoxybenzonitrile SM to prepare a compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I; the synthetic route is as follows:
The preparation method of the ozagrel hydrochloride key intermediate I shown in the formula (I) comprises the following steps:
At room temperature, adding tert-butyl (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamate I-2, 5-formyl-2-isopropoxy benzonitrile SM and alkali into dimethyl sulfoxide, controlling the temperature to react T B, pouring the reaction liquid into purified water after the detection reaction is finished, extracting dichloromethane, and concentrating the organic phase under reduced pressure until the organic phase is dried to obtain the compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamate I.
Preferably, the alkali is one of sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably potassium hydroxide. Wherein the base may be a hydrate thereof, such as lithium hydroxide monohydrate.
Preferably, the feeding mole ratio of the (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-inden-1-yl) carbamic acid tert-butyl ester I-2 to the 5-formyl-2-isopropoxy benzonitrile SM is 1:1.6 to 3.0, preferably 1:2.2.
Preferably, the feeding mole ratio of the (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-inden-1-yl) carbamic acid tert-butyl ester I-2 to the alkali is 1:1.4 to 2.5, preferably 1:1.8.
Preferably, the reaction temperature T B is 15 to 50 ℃, preferably 25 to 30 ℃.
Wherein the compound (S) -tert-butyl 2- (tert-butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-inden-1-yl) carbamic acid tert-butyl ester I-2 can be prepared according to the prior art or according to the following schemes and methods.
Adding a compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4-cyano-2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-1, hydroxylamine hydrochloride and an acid binding agent into a dry reaction solvent A at room temperature, controlling the temperature to react with T A, filtering the reaction liquid after the detection reaction is finished, concentrating under reduced pressure to remove the reaction solvent A, adding purified water, extracting with an extracting agent, and concentrating an organic phase under reduced pressure until the organic phase is dried to obtain a compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2; the synthetic route is as follows:
Preferably, the acid binding agent is one or a combination of triethylamine, potassium carbonate and sodium carbonate, preferably potassium carbonate.
Preferably, the reaction solvent A is one or a combination of methanol, ethanol, isopropanol and tertiary butanol, preferably tertiary butanol.
Preferably, the feeding mole ratio of the compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4-cyano-2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-1 to hydroxylamine hydrochloride and the acid binding agent is 1:1.5 to 3.5:1.5 to 3.5, preferably 1:2.4:2.4.
Preferably, the reaction temperature T A is 50 to 85 ℃, preferably 80 to 85 ℃.
Preferably, the extractant used for the post-treatment is one or a combination of dichloromethane, chloroform, ethyl acetate and methyl tertiary butyl ether, and preferably dichloromethane.
The invention has the beneficial effects that:
1. The invention provides a simple and efficient method for preparing an ozagrel hydrochloride key intermediate I, wherein (S) -2- (tert-butyl dimethyl siloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 and 5-formyl-2-isopropoxy benzonitrile SM are prepared into a target product by forming 1,2, 4-oxadiazole ring under the strong alkaline condition, and the whole synthesis method is simple and convenient to operate and suitable for industrial production.
2. The process does not need condensing agent in the cyclization step, so that the target product has no residue of condensing agent byproducts; the 5-formyl-2-isopropoxy benzonitrile SM aldehyde group compound is selected, and side reactions caused by the selection of substrates with acid or acyl chloride and the like in the prior art are avoided. The obtained product has high purity and high yield.
Drawings
FIG. 1 is a 1 H-NMR spectrum of intermediate I of the invention.
FIG. 2 is a 13 C-NMR spectrum of intermediate I of the invention.
FIG. 3 is a mass spectrum of intermediate I of the present invention.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
In the following examples, various processes and methods, which are not described in detail, are conventional methods well known in the art.
Synthesis of I-2:
Example 1
The compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4-cyano-2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-1 (41.66 g,0.1 mol), hydroxylamine hydrochloride (16.68 g,0.24 mol) and potassium carbonate (33.17 g,0.24 mol) are added into dry tert-butyl alcohol (400 ml) at room temperature, the temperature is controlled between 80 and 85 ℃, after the reaction is completed, the reaction solution is filtered and concentrated under reduced pressure to remove the reaction solvent, purified water (300 ml) is added, dichloromethane (100 ml x 3) is added for extraction, and the organic phase is concentrated under reduced pressure until the organic phase is dried to obtain the compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2, the yield of which is 99.6 percent and the purity is 98.85 percent.
Synthesis of I
Example 2
(S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 (22.48 g,0.05 mol), 5-formyl-2-isopropoxybenzonitrile SM (20.81 g,0.11 mol), potassium hydroxide (5.05 g,0.09 mol) were added to dimethyl sulfoxide (250 ml) at room temperature, the temperature was controlled at 25-30 ℃, after the completion of the detection reaction, the reaction solution was poured into purified water (2000 ml), methylene chloride (600 ml. Times.3) was extracted, and the organic phase was concentrated under reduced pressure to dryness to obtain the compound (S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I with a yield of 95.8% and a purity of 99.58% by HPLC.
Example 3
(S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 (22.48 g,0.05 mol), 5-formyl-2-isopropoxybenzonitrile SM (15.14 g,0.08 mol), potassium hydroxide (5.05 g,0.09 mol) were added to dimethyl sulfoxide (250 ml) at room temperature, the temperature was controlled at 25-30 ℃, after the completion of the detection reaction, the reaction solution was poured into purified water (2000 ml), methylene chloride (600 ml. Times.3) was extracted, and the organic phase was concentrated under reduced pressure to dryness to obtain the compound (S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I with a yield of 93.6% and a purity of 99.15% by HPLC.
Example 4
(S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 (22.48 g,0.05 mol), 5-formyl-2-isopropoxybenzonitrile SM (14.19 g,0.075 mol), potassium hydroxide (5.05 g,0.09 mol) were added to dimethyl sulfoxide (250 ml) at room temperature, the reaction was controlled at 25-30℃and after the completion of the detection reaction, the reaction solution was poured into purified water (2000 ml), methylene chloride (600 ml. Times.3) was extracted, and the organic phase was concentrated under reduced pressure to dryness to give the compound (S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I in 91.5% yield and 99.05% purity.
Example 5
(S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 (22.48 g,0.05 mol), 5-formyl-2-isopropoxybenzonitrile SM (28.38 g,0.15 mol), potassium hydroxide (5.05 g,0.09 mol) were added to dimethyl sulfoxide (250 ml) at room temperature, the temperature was controlled to 20-25 ℃, after the completion of the detection reaction, the reaction solution was poured into purified water (2000 ml), methylene chloride (600 ml. Times.3) was extracted, and the organic phase was concentrated under reduced pressure to dryness to obtain the compound (S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I with a yield of 95.6% and a purity of 99.26% by HPLC.
Example 6
(S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 (22.48 g,0.05 mol), 5-formyl-2-isopropoxybenzonitrile SM (29.33 g,0.155 mol), lithium hydroxide monohydrate (3.78 g,0.09 mol) were added to dimethyl sulfoxide (250 ml) at room temperature, the reaction was carried out at 15-20℃under controlled temperature, after the completion of the detection reaction, the reaction solution was poured into purified water (2000 ml), methylene chloride (600 ml. Times.3) was extracted, and the organic phase was concentrated to dryness under reduced pressure to give the compound (S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I, yield 95.7%, purity was 95.7% by HPLC.
Example 7
(S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 (22.48 g,0.05 mol), 5-formyl-2-isopropoxybenzonitrile SM (23.65 g,0.125 mol), potassium hydroxide (3.93 g,0.07 mol) were added to dimethyl sulfoxide (250 ml) at room temperature, the temperature was controlled at 25-30 ℃, after the completion of the detection reaction, the reaction solution was poured into purified water (2000 ml), methylene chloride (600 ml. Times.3) was extracted, and the organic phase was concentrated under reduced pressure to dryness to obtain the compound (S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I with a yield of 94.6% and a purity of 99.44% by HPLC.
Example 8
(S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 (22.48 g,0.05 mol), 5-formyl-2-isopropoxybenzonitrile SM (23.65 g,0.125 mol), potassium hydroxide (7.01 g,0.125 mol) were added to dimethyl sulfoxide (250 ml) at room temperature, the temperature was controlled at 25-30 ℃, after the completion of the detection reaction, the reaction solution was poured into purified water (2000 ml), methylene chloride (600 ml. Times.3) was extracted, and the organic phase was concentrated under reduced pressure to dryness to obtain the compound (S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I with a yield of 95.6% and a purity of 99.33% by HPLC.
Example 9
(S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 (22.48 g,0.05 mol), 5-formyl-2-isopropoxybenzonitrile SM (20.81 g,0.11 mol), potassium hydroxide (5.05 g,0.09 mol) were added to dimethyl sulfoxide (250 ml) at room temperature, the temperature was controlled to 15-20 ℃, after the completion of the detection reaction, the reaction solution was poured into purified water (2000 ml), methylene chloride (600 ml. Times.3) was extracted, and the organic phase was concentrated under reduced pressure to dryness to obtain the compound (S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I with a yield of 95.3% and a purity of 99.23% by HPLC.
Example 10
(S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 (22.48 g,0.05 mol), 5-formyl-2-isopropoxybenzonitrile SM (20.81 g,0.11 mol), potassium hydroxide (5.05 g,0.09 mol) were added to dimethyl sulfoxide (250 ml) at room temperature, the temperature was controlled at 40-45 ℃, after the completion of the detection reaction, the reaction solution was poured into purified water (2000 ml), methylene chloride (600 ml. Times.3) was extracted, and the organic phase was concentrated under reduced pressure to dryness to obtain the compound (S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I with a yield of 94.8% and a purity of 99.12% by HPLC.
Example 11
(S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 (22.48 g,0.05 mol), 5-formyl-2-isopropoxybenzonitrile SM (20.81 g,0.11 mol), lithium hydroxide monohydrate (3.78 g,0.09 mol) were added to dimethyl sulfoxide (250 ml) at room temperature, the reaction was carried out at 25 to 30℃under controlled temperature, after the completion of the detection reaction, the reaction solution was poured into purified water (2000 ml), methylene chloride (600 ml. Times.3) was extracted, and the organic phase was concentrated to dryness under reduced pressure to give the compound (S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I, yield 95.6%, purity of 95.44% by HPLC.
Example 12
(S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 (22.48 g,0.05 mol), 5-formyl-2-isopropoxybenzonitrile SM (20.81 g,0.11 mol) and sodium hydroxide (3.60 g,0.09 mol) are added into dimethyl sulfoxide (250 ml) at room temperature, reaction is carried out at a temperature of 25-30 ℃, after the detection reaction is finished, the reaction solution is poured into purified water (2000 ml), dichloromethane (600 ml multiplied by 3) is extracted, and the organic phase is decompressed and concentrated to dryness to obtain the compound (S) -2- (tert-Butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I with the yield of 95.7% and the purity of 99.40% by HPLC.
Claims (7)
1. A preparation method of an ozagrel hydrochloride key intermediate I shown in a formula (I) is characterized in that a compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 is reacted with 5-formyl-2-isopropoxybenzonitrile SM to prepare a compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I; the synthetic route is as follows:
2. the preparation method according to claim 1, characterized in that the preparation method comprises the steps of:
At room temperature, adding tert-butyl (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamate I-2, 5-formyl-2-isopropoxy benzonitrile SM and alkali into dimethyl sulfoxide, controlling the temperature to react T B, pouring the reaction liquid into purified water after the detection reaction is finished, extracting dichloromethane, and concentrating the organic phase under reduced pressure until the organic phase is dried to obtain the compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) -2, 3-dihydro-1H-indene-1-yl) carbamate I.
3. The method according to claim 1, wherein the base is one of sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably potassium hydroxide.
4. The preparation method according to claim 1, wherein the molar ratio of the (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-inden-1-yl) carbamic acid tert-butyl ester I-2 to the 3-cyano-4-isopropoxybenzaldehyde SM is 1:1.6 to 3.0, preferably 1:2.2.
5. The preparation method according to claim 1, wherein the molar ratio of the (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-2 to the base is 1:1.4 to 2.5, preferably 1:1.8.
6. The process according to claim 1, wherein the reaction temperature T B is 15 to 50 ℃, preferably 25 to 30 ℃.
7. The process according to claim 1, wherein the compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4- (N-hydroxy-formamidino) -2, 3-dihydro-1H-inden-1-yl) carbamic acid tert-butyl ester I-2 is prepared by: is prepared by the reaction of a compound (S) -2- (tert-butyldimethylsilyloxy) ethyl (4-cyano-2, 3-dihydro-1H-indene-1-yl) carbamic acid tert-butyl ester I-1 and hydroxylamine hydrochloride; the synthetic route is as follows:
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