CN102060749B - Preparation method of 2-cyan-7-aza-spiro[3,5]nonane derivative - Google Patents
Preparation method of 2-cyan-7-aza-spiro[3,5]nonane derivative Download PDFInfo
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- CN102060749B CN102060749B CN 200910201786 CN200910201786A CN102060749B CN 102060749 B CN102060749 B CN 102060749B CN 200910201786 CN200910201786 CN 200910201786 CN 200910201786 A CN200910201786 A CN 200910201786A CN 102060749 B CN102060749 B CN 102060749B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- OUXRPSUPWKNBLL-UHFFFAOYSA-N 7-azaspiro[3.5]nonane-2-carbonitrile Chemical class C1C(C#N)CC21CCNCC2 OUXRPSUPWKNBLL-UHFFFAOYSA-N 0.000 title abstract 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 10
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 7
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000001412 amines Chemical class 0.000 claims abstract description 7
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 claims abstract description 7
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 7
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 7
- 239000010703 silicon Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 4
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 239000007795 chemical reaction product Substances 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 44
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical class CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 11
- -1 piperidines formaldehyde derivatives Chemical class 0.000 claims description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 4
- 238000000034 method Methods 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 229910052751 metal Inorganic materials 0.000 abstract description 4
- 239000002184 metal Substances 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 abstract 2
- 238000001308 synthesis method Methods 0.000 abstract 2
- FEWLNYSYJNLUOO-UHFFFAOYSA-N 1-Piperidinecarboxaldehyde Chemical class O=CN1CCCCC1 FEWLNYSYJNLUOO-UHFFFAOYSA-N 0.000 abstract 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 230000007547 defect Effects 0.000 abstract 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 7
- 238000003810 ethyl acetate extraction Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000012266 salt solution Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- WSBLSUZIPMSRLJ-UHFFFAOYSA-N 1-isocyanoethylsulfonylbenzene Chemical compound [C-]#[N+]C(C)S(=O)(=O)C1=CC=CC=C1 WSBLSUZIPMSRLJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- YHFRNYULFUZKJG-UHFFFAOYSA-N isocyanosulfonylmethane Chemical compound CS(=O)(=O)[N+]#[C-] YHFRNYULFUZKJG-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a new synthesis method of a 2-cyan-7-aza-spiro[3,5]nonane derivative. The new synthesis method overcomes the defects of instable yield, severe pollution, difficulty in purification, low yield and the like in the conventional synthesis process metal catalysis. A preparation method of the 2-cyan-7-aza-spiro[3,5]nonane derivative comprises the following steps of: 1, reacting a piperidinyl formaldehyde derivative serving as an initiative raw material and benzyltrimethylammonium hydroxide serving as an alkali with acrylonitrile to obtain a 4-propionitrile-4-formaldehyde piperidine derivative; 2, reacting the product obtained in the step 1 with sodium borohydride in ethanol solution at room temperature to reduce aldehyde into alcohol; 3, reacting the reduced alcohol with paratoluensulfonylchloride at room temperature by using 4-dimethylamino pyridine as a catalyst to protect hydroxyl; and 4, performing ring-closing reaction on the reaction product obtained in the step 3 and hexamethyl silicon amine lithium at the temperature of between -78 DEG C and room temperature to obtain the 2-cyan-7-aza-spiro[3,5]nonane derivative. The 2-cyan-7-aza-spiro[3,5]nonane derivative prepared by the method is a useful intermediate or product applied to synthesis of a plurality of medicaments.
Description
Technical field
The present invention relates to the new synthetic method of 2-cyano group-7-azepine-spiral shell [3,5] nonane derivatives.
Background technology
The cyano compound of volution has widespread use in pharmaceutical chemistry and organic synthesis.Can access corresponding amino and acid compounds after cyano reduction and the hydrolysis, it is synthetic useful intermediates or products of many medicines.
The synthetic method of this compound is starting raw material with the vinyl compound at present, and the implementation procedure of the first step is comparatively difficult in this method, and it relates to metal catalytic, and is seriously polluted, and yield is difficult to guarantee.Need to use after obtaining ketone compounds Methyl benzenesulfonyl methyl isonitrile is become cyano group with it, this reaction yield is low, and it is comparatively complicated that it handles purge process.Its reaction formula is as follows:
Therefore, need one of exploitation simpler, reaction conditions and yield are comparatively stable, easily the method for purifying.
Summary of the invention
The objective of the invention is to develop a kind of novel method for the preparation of 2-cyano group-7-azepine-spiral shell [3,5] nonane derivatives, mainly solve the metal catalytic that present synthesis technique exists and cause the yield instability, pollute technical problems such as big, difficult purifying, yield are low.
Technical scheme of the present invention: the present invention is starting raw material with the piperidines formaldehyde derivatives, the first step: do alkali (0.1-1 equivalent) with benzyltrimethylammonium hydroxide, at-10 ~ 25 ℃, through reacting 1 ~ 5 hour with vinyl cyanide (2 equivalent), obtain 4-propionitrile-4-carboxaldehyde radicals piperidine derivative; In second step, the previous step product is in ethanolic soln, and under the room temperature, the sodium borohydride reaction by 1.2 equivalents 5 hours is reduced to alcohol with aldehyde; The 3rd step was catalyzer (0.1 equivalent) with the 4-Dimethylamino pyridine, at room temperature, and the pure and mild Methanesulfonyl chloride after the reduction (1.2 equivalent) reaction protection in 2 hours hydroxyl; The 4th step, under-78 ℃ ~ room temperature (10-30 ℃) and hexamethyl silicon amine lithium (1.1 ~ 2.0 equivalent) reaction closed ring in 5 ~ 8 hours and obtain 2-cyano group-7-azepine-spiral shell [3,5] nonane derivatives.Reaction formula is as follows:
。
Beneficial effect of the present invention: the invention solves in the synthesis technique of both having known at present and relate to metal catalytic, seriously polluted, yield is difficult to guarantee.And with the methyl sulphonyl isocyanide it is become cyano group, reaction yield is low, handles comparatively shortcoming such as complexity of purge process.Be starting raw material with the piperidines formaldehyde derivatives, can realize 2-cyano group-7-azepine-spiral shell [3,5] nonane derivatives laboratory preparation and industrial large-scale production fast.
Embodiment
Step 1
Example 1:
Under-10 ℃, benzyltrimethylammonium hydroxide (10 mL, 40 % methanol solutions) slowly is added drop-wise to compound 1 (60 g, 0.282 mol) and vinyl cyanide (30 g, 0.566 mol) anhydrous 1, in 4-dioxane (300 mL) solution, and reaction 5 hours under room temperature.After reaction finishes, with saturated ammonium chloride (500 mL) cancellation reaction, and use ethyl acetate extraction, organic phase with 1M HCl, saturated sodium bicarbonate and salt solution wash, drying, be concentrated into dried compound 2 (48.7 g, yield 65%).
Example 2:
Under 0 ℃, benzyltrimethylammonium hydroxide (30 mL, 40 % methanol solutions) slowly is added drop-wise to compound 1 (60 g, 0.282 mol) and vinyl cyanide (30 g, 0.566 mol) anhydrous 1, in 4-dioxane (300 mL) solution, and reaction 3 hours under room temperature.After reaction finishes, with saturated ammonium chloride cancellation reaction, and use ethyl acetate extraction, organic phase with 1M HCl, saturated sodium bicarbonate and salt solution wash, drying, be concentrated into dried compound 2 (56.3 g, yield 75%).
Example 3:
Under 25 ℃, benzyltrimethylammonium hydroxide (100 mL, 40 % methanol solutions) slowly is added drop-wise to compound 1 (60 g, 0.282 mol) and vinyl cyanide (30 g, 0.566 mol) anhydrous 1, in 4-dioxane (300 mL) solution, and reaction 1 hour under room temperature.After reaction finishes, with saturated ammonium chloride cancellation reaction, and use ethyl acetate extraction, organic phase with 1M HCl, saturated sodium bicarbonate and salt solution wash, drying, be concentrated into dried compound 2 (58g, yield 77%), be directly used in next step.
Step 2
Example 1:
Under 25 ℃, with NaBH
4(9.5 g, 0.25 mol) slowly joins in dehydrated alcohol (600 mL) solution of compound 2 (56.3 g, 0.21 mol), room temperature reaction 5 hours.Reaction slowly is poured into reaction solution in the frozen water after finishing, and transfers pH=3-4 with 1M HCl, uses ethyl acetate extraction then.Organic phase gets compound 3 (53.5g, yield 95 %) with saturated common salt water washing, drying, chromatography column purifying.
Step 3
Example 1:
Under 0 ℃, Methanesulfonyl chloride (27.1 g, 0.24 mol) slowly is added drop-wise to compound 3 (53.5 g, 0.2 mol), Et
3In anhydrous methylene chloride (500 mL) solution of N (50g, 0.5 mol) and 4-dimethylamino pyridine (1 g, 0.02 mol), room temperature reaction 2 hours, TLC are followed the tracks of reaction to finishing.With reaction solution water, 1 M HCl and saturated common salt water washing, be concentrated into dried compound 4 (62.3g, yield 90%).
Step 4
。
Example 1:
-78 ℃, under the nitrogen protection, hexamethyl silicon amine lithium (190 mL, 0.19 mol) slowly is added drop-wise to compound 4, and (62.3g, in anhydrous tetrahydro furan 0.18mol) (600 mL) solution ,-78 ℃ to room temperature reaction 5 hours.Reaction is used saturated NH after finishing
4Cl cancellation reaction, ethyl acetate extraction, organic phase with the salt solution washing, concentrate, the chromatography column purifying gets product 5 (20g, yield 45 %).
Example 2:
-78 ℃, under the nitrogen protection, hexamethyl silicon amine lithium (285 mL, 0.285 mol) slowly is added drop-wise to compound 4, and (62.3g, in anhydrous tetrahydro furan 0.18mol) (600 mL) solution ,-78 ℃ to room temperature reaction 8 hours.Reaction is used saturated NH after finishing
4Cl cancellation reaction, ethyl acetate extraction, organic phase with the salt solution washing, concentrate, the chromatography column purifying gets product 5 (24.7g, yield 55 %).
Example 3:
-78 ℃, under the nitrogen protection, hexamethyl silicon amine lithium (380 mL, 0.38 mol) slowly is added drop-wise to compound 4, and (62.3g, in anhydrous tetrahydro furan 0.18mol) (600 mL) solution ,-78 ℃ to room temperature reaction 8 hours.Reaction is used saturated NH after finishing
4Cl cancellation reaction, ethyl acetate extraction, organic phase with the salt solution washing, concentrate, the chromatography column purifying gets product 5 (25.6g, 57 %).
Claims (5)
1. 2-cyano group-7-azepine-spiral shell [3,5] preparation method of nonane derivatives, may further comprise the steps: the first step reaction: be starting raw material with the piperidines formaldehyde derivatives, do alkali with benzyltrimethylammonium hydroxide, obtain 4-propionitrile-4-carboxaldehyde radicals piperidine derivative with acrylonitrile reactor; The reaction of second step, 4-propionitrile-4-carboxaldehyde radicals piperidine derivative with the sodium borohydride reaction, are reduced to alcohol with aldehyde in ethanolic soln; Three-step reaction is catalyzer with the 4-Dimethylamino pyridine, the pure and mild Methanesulfonyl chloride reaction protection hydroxyl after the reduction; Four-step reaction, three-step reaction product and the reaction of hexamethyl silicon amine lithium are closed ring and are obtained 2-cyano group-7-azepine-spiral shell [3,5] nonane derivatives.
2. 2-cyano group according to claim 1-7-azepine-spiral shell [3,5] preparation method of nonane derivatives, it is characterized in that: described the first step reaction, the benzyltrimethylammonium hydroxide consumption is 0.1～1 equivalent, the vinyl cyanide consumption is 2 equivalents, temperature of reaction-10～25 ℃, 1～5 hour reaction times.
3. the preparation method of 2-cyano group according to claim 1-7-azepine-spiral shell [3,5] nonane derivatives is characterized in that: described second step reaction, and the sodium borohydride consumption is 1.2 equivalents, the reaction times is 5 hours.
4. 2-cyano group according to claim 1-7-azepine-spiral shell [3,5] preparation method of nonane derivatives is characterized in that: described three-step reaction, and 4-Dimethylamino pyridine consumption is 0.1 equivalent, the Methanesulfonyl chloride consumption is 1.2 equivalents, and the reaction times is 2 hours.
5. 2-cyano group according to claim 1-7-azepine-spiral shell [3,5] preparation method of nonane derivatives is characterized in that: described four-step reaction, hexamethyl silicon amine lithium consumption 1.1～2.0 equivalents, temperature of reaction is at-78 ℃～30 ℃, and the reaction times is 5～8 hours.
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| CN116396191A (en) * | 2023-04-07 | 2023-07-07 | 阜阳欣奕华制药科技有限公司 | Preparation method of N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester derivative |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1275124A (en) * | 1998-02-19 | 2000-11-29 | 卫材株式会社 | Phthalazine derivatives and remedies for erectile dysfunction |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1275124A (en) * | 1998-02-19 | 2000-11-29 | 卫材株式会社 | Phthalazine derivatives and remedies for erectile dysfunction |
Non-Patent Citations (2)
| Title |
|---|
| Toshihiko KANEKO，et al.."Piperidine Carboxylic Acid Derivatives of 10H-Pyrazino[2,3-b][1,4]benzothiazine as Orally-Active Adhesion Molecule Inhibitors".《Chem. Pharm. Bull.》.2004,第52卷(第6期),p675-687. |
| Toshihiko KANEKO,et al.."Piperidine Carboxylic Acid Derivatives of 10H-Pyrazino[2,3-b][1,4]benzothiazine as Orally-Active Adhesion Molecule Inhibitors".《Chem. Pharm. Bull.》.2004,第52卷(第6期),p675-687. * |
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