CN106892928B - A kind of synthetic method of tertiary butyl -8- hydroxyls -5- oxa- -2- azaspiros [3.5] nonane -2- carboxylates - Google Patents
A kind of synthetic method of tertiary butyl -8- hydroxyls -5- oxa- -2- azaspiros [3.5] nonane -2- carboxylates Download PDFInfo
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- CN106892928B CN106892928B CN201710066748.5A CN201710066748A CN106892928B CN 106892928 B CN106892928 B CN 106892928B CN 201710066748 A CN201710066748 A CN 201710066748A CN 106892928 B CN106892928 B CN 106892928B
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- hydroxyls
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 11
- KUSYIGBGHPOWEL-UHFFFAOYSA-N 2-methyl nonaoic acid Chemical class CCCCCCCC(C)C(O)=O KUSYIGBGHPOWEL-UHFFFAOYSA-N 0.000 title claims description 10
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 title claims description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims abstract description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940125782 compound 2 Drugs 0.000 claims abstract description 9
- 229940126214 compound 3 Drugs 0.000 claims abstract description 8
- 229940125904 compound 1 Drugs 0.000 claims abstract description 5
- 229940125898 compound 5 Drugs 0.000 claims abstract description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- 238000006385 ozonation reaction Methods 0.000 claims abstract description 3
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 3
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 3
- -1 butyl 2 azaspiro [3.5] nonane Chemical group 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 238000007792 addition Methods 0.000 claims description 6
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 2
- 150000007942 carboxylates Chemical class 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 238000003756 stirring Methods 0.000 description 12
- 239000012043 crude product Substances 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 4
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- TWJVNKMWXNTSAP-UHFFFAOYSA-N azanium;hydroxide;hydrochloride Chemical class [NH4+].O.[Cl-] TWJVNKMWXNTSAP-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention relates to the synthetic methods of 5 oxa- of a kind of 8 hydroxyl of tertiary butyl 2 azaspiro [3.5] nonane, 2 carboxylate, the technical issues of mainly solution currently without suitable Industrialized synthesis method.Product of the present invention has extensive use in pharmaceutical chemistry and organic synthesis.The present invention divides four steps, first by compound 1 under n-BuLi alkaline condition and 3 methyl, 3 butylene, 1 alcohol addition, obtain compound 2, then n-BuLi cyclization is used to generate compound 3, then 3 ozonization of compound obtains compound 4, and final compound 5 is obtained with sodium borohydride reduction carbonyls 4.Reaction equation is as follows：
Description
Technical field
Compound tert-butyl group -8- hydroxyls -5- oxa- -2- azaspiros [3.5] nonane -2- carboxylates of the present invention
Synthetic method.
Background technology
Compound tert-butyl group -8- hydroxyls -5- oxa- -2- azaspiros [3.5] nonane -2- carboxylates（CAS :1779396-
21-2）And relevant derivative has extensive use in pharmaceutical chemistry and organic synthesis.Tertiary butyl -8- hydroxyls -5- oxygen at present
Miscellaneous -2- azaspiros [3.5] nonane -2- carboxylate industry is combined to no document report.It is easy therefore, it is necessary to develop a raw material
, easy to operate, reaction is easily controllable, and overall yield is suitble to, and is suitble to the synthetic method of industrialized production.
Invention content
The purpose of the present invention is exploitation one kind to be easy to get with raw material, easy to operate, reacts easily controllable, the higher uncle of yield
The synthetic method of butyl -8- hydroxyls -5- oxa- -2- azaspiros [3.5] nonane -2- carboxylates.It mainly solves currently without suitable
The technical issues of closing Industrialized synthesis method.
Technical scheme of the present invention：A kind of tertiary butyl -8- hydroxyls -5- oxa- -2- azaspiros [3.5] nonane -2- carboxylic acids
The synthetic method of ester, the present invention divide four steps, the first step, by compound 1 under n-BuLi alkaline condition and 3- methyl -3- fourths
Alkene -1- alcohol additions, obtain compound 2, second step, and the n-BuLi cyclization of compound 2 generates compound 3, third step, compound
3 ozonizations obtain compound 4, and the 4th step obtains final compound 5 with sodium borohydride reduction carbonyls 4.Reaction
Formula is as follows：
Solvent in reaction equation is one kind in tetrahydrofuran, ethyl acetate, methanol, dichloromethane or water；The first step is anti-
It is tetrahydrofuran to answer middle solvent, and research finds that tetramethylethylenediamine, which is added, reinforces alkalinity, is conducive to reaction and carries out；Second step reaction is molten
The preferred tetrahydrofuran of agent；When third step research finds that solvent is methanol, the reaction time can be shortened；The preferred first of four-step reaction solvent
Alcohol；Room temperature reaction 1 hour.
The Chinese paraphrase that the present invention abridges：TLC：Thin-layered chromatography, Rf ：Rf value.
Beneficial effects of the present invention：Reaction process reasonable design of the present invention, which employs be easy to get, can large-scale production original
Expect 1-Boc-3- aza cyclo-butanones, passes through four step synthesizing tertiary butyl -8- hydroxyls -5- oxa- -2- azaspiros [3.5] nonane -2-
The method of carboxylate, this method route is short, and yield may be up to 6.9%, and reaction is easy to amplify, easy to operate.
Specific implementation mode
Reaction equation of the present invention is as follows：
。
Embodiment 1：N-BuLi (697 mL, 174.3 mmol, 2.5 M) is dissolved in tetrahydrofuran (900 mL)
In, then 3- methyl-3-butene-1-alcohols (500 g, 5.81 mol) and tetramethylethylenediamine is added dropwise for 0-10 degrees Celsius
(20.25 g, 17.4 mmol) are dissolved in tetrahydrofuran（200 mL）Mixture, be added dropwise, stir 1h, then 0-10 takes the photograph
Compound 1 is added dropwise in family name's degree（107 g, 62.7 mmol）It is dissolved in tetrahydrofuran (200 mL), is then stirred at 0-10 degrees Celsius
2h.TLC (petrol ether/ethyl acetate volume ratios=3/1, Rf=0.1) display reaction finishes.Saturated aqueous ammonium chloride
（500 mL）Dropwise addition is quenched, ethyl acetate（500 mL）Extraction 3 times, organic phase dries to obtain crude product, and three batches are thick
Product silica gel chromatograph column purification（Petrol ether/ethyl acetate volume ratio=5:1~0:1）Crude Compound 2 is obtained（120.4
g）, yield：25.3%.
Compound 2 (25.3 g, 93.82 mmol) is dissolved in tetrahydrofuran (110 mL）, in -40 degrees Celsius of nitrogen
Protection is lower to be added dropwise n-BuLi (39.33 mL, 98.32 mmol, 2.5 M), is added dropwise, stirs 0.5h, then -40 take the photograph
Paratoluensulfonyl chloride is added dropwise in family name's degree（18.74 g, 98.32 mmol）It is dissolved in tetrahydrofuran (20 mL), is added dropwise, is taken the photograph 0
After stirring 0.5h under family name's degree, then n-BuLi (39.33 mL, 98.32 mmol, 2.5 M) is added dropwise, this mixture exists
4h is stirred under 25 degrees Celsius.TLC (petrol ether/ethyl acetate volume ratios=3/1, Rf=0.8) display reaction finishes.
Saturated aqueous ammonium chloride（500 mL）Dropwise addition is quenched, three batch reaction solution ethyl acetate（500 mL）Extraction 3 times,
Organic phase dries to obtain crude product, crude product silica gel chromatograph column purification（Petrol ether/ethyl acetate volume ratio=20:1~
5:1）Crude Compound 3 is obtained（79.3 g）, yield：54.3%.
Compound 3 (10 g, 41.78 mmol) is dissolved in dichloromethane (150 mL）And methanol（5 mL）, -78
Degree Celsius it is passed through ozone 1.3h, then passes to oxygen and remove ozone, dimethyl sulphide is added dropwise at -78 degrees Celsius and at 20 degrees Celsius
Stir 1h.TLC (petrol ether/ethyl acetate volume ratios=5/1, Rf=0.1) display reaction finishes.This reaction adds
Enter water（40 mL）Dichloromethane is used in combination（50 mL）Extraction 3 times, organic phase dry to obtain crude product, and two batch crude products are used
Silica gel chromatograph column purification（Petrol ether/ethyl acetate volume ratio=8:1~3:1）Obtain compound 4（13.2 g）, receive
Rate：59.3%.
Compound 4 (9.8 g, 40.61 mmol) is dissolved in methanol (100 mL）, boron hydrogen is added portionwise at 0 degree Celsius
Change sodium (0.46 g, 12.18 mmol), 25 degrees Celsius of stirring 1h.TLC (petrol ether/ethyl acetate volume ratio=1/1,
Rf=0.3) display reaction finishes.It is added dropwise and water is added（50 mL）It is quenched and is removed most of solvent, water is then added
（30 mL）It is used in combination ethyl acetate (50 mL) to extract 3 times, organic phase dries to obtain compound 5（9.02 g）, yield：
92.0%。
1CDCl3, δ 1.33-1.44 (m, 9 H) 1.46-1.58 (m, 1 H) 1.66 (dd, J=12.57,
9.48 Hz, 1 H) 1.78 - 1.90 (m, 1 H) 2.03 (s, 1 H) 2.12 (dd, J=12.79, 2.21 Hz,
1 H) 3.38 - 3.53 (m, 1 H) 3.67 - 3.76 (m, 1 H) 3.77 - 3.96 (m, 5 H)。
Embodiment 2：N-BuLi (6972 mL, 17.43 mol, 2.5 M) is dissolved in tetrahydrofuran (9000 mL)
In, then 3- methyl-3-butene-1-alcohols (500 g, 5.81 mol) and tetramethylethylenediamine is added dropwise for 0-10 degrees Celsius
(202.54 g, 1.74 mol) are dissolved in tetrahydrofuran（2000 mL）Mixture, be added dropwise, stir 1h, then 0-10
Degree Celsius be added dropwise compound 1（1.07 Kg, 6.27 mol）It is dissolved in tetrahydrofuran (2000 mL), then at 0-10 degrees Celsius
Stir 2h.TLC (petrol ether/ethyl acetate volume ratios=3/1, Rf=0.1) display reaction finishes.Saturated ammonium chloride water
Solution（5 L）Dropwise addition is quenched, ethyl acetate（5 L）Extraction 3 times, organic phase dries to obtain crude product, three batch crude products
Silica gel chromatograph column purification（Petrol ether/ethyl acetate volume ratio=5:1~0:1）Crude Compound 2 is obtained（1.13
Kg）, yield：25.08%.
Compound 2 (253 g, 938.17 mmol) is dissolved in tetrahydrofuran (1.1 L）, protected in -40 degrees Celsius of nitrogen
Shield is lower to be added dropwise n-BuLi (393.27 mL, 983.17 mmol, 2.5 M), is added dropwise, stirs 0.5h, then -40 take the photograph
Paratoluensulfonyl chloride is added dropwise in family name's degree（187.44 g, 983.17 mmol）It is dissolved in tetrahydrofuran (200 mL), is added dropwise,
After stirring 0.5h under 0 degree Celsius, then n-BuLi (393.27 mL, 983.17 mmol, 2.5 M) is added dropwise, this mixing
Object stirs 4h under 25 degrees Celsius.TLC (petrol ether/ethyl acetate volume ratios=3/1, Rf=0.8) display has been reacted
Finish.Saturated aqueous ammonium chloride（500 mL）Dropwise addition is quenched, three batch reaction solution ethyl acetate（5 L）Extraction 3 times,
Organic phase dries to obtain crude product, crude product silica gel chromatograph column purification（Petrol ether/ethyl acetate volume ratio=20:1~
5:1）Crude Compound 3 is obtained（750 g）, yield：53.1%.
Compound 3 (100 g, 417.87 mmol) is dissolved in dichloromethane (1500 mL）And methanol（50 mL）,
It is passed through ozone 1.3h at -78 degrees Celsius, then passes to oxygen and removes ozone, dimethyl sulphide is added dropwise at -78 degrees Celsius and 20
Degree Celsius stirring 1h.TLC (petrol ether/ethyl acetate volume ratios=5/1, Rf=0.1) display reaction finishes.This
Water is added in reaction（200 mL）Dichloromethane is used in combination（500 mL）Extraction 3 times, organic phase dry to obtain crude product, and two are criticized
Secondary crude product silica gel chromatograph column purification（Petrol ether/ethyl acetate volume ratio=8:1~3:1）Obtain compound 4（117
g）, yield：58.02%.
Compound 4 (98 g, 406.17 mmol) is dissolved in methanol (1 L）, hydroboration is added portionwise at 0 degree Celsius
Sodium (4.61 g, 121.85 mmol), 25 degrees Celsius of stirring 1h.TLC (petrol ether/ethyl acetate volume ratio=1/1,
Rf=0.3) display reaction finishes.It is added dropwise and water is added（100 mL）It is quenched and is removed most of solvent, water is then added
（300 mL）It is used in combination ethyl acetate (500 mL) to extract 3 times, organic phase dries to obtain compound 5（90 g）, yield：
91.8%。
1CDCl3, δ 1.33-1.44 (m, 9 H) 1.46-1.58 (m, 1 H) 1.66 (dd, J=12.57,
9.48 Hz, 1 H) 1.78 - 1.90 (m, 1 H) 2.03 (s, 1 H) 2.12 (dd, J=12.79, 2.21 Hz,
1 H) 3.38 - 3.53 (m, 1 H) 3.67 - 3.76 (m, 1 H) 3.77 - 3.96 (m, 5 H)。
Claims (4)
1. a kind of synthetic method of tertiary butyl -8- hydroxyls -5- oxa- -2- azaspiros [3.5] nonane -2- carboxylates, feature
It is to include the following steps：The first step, by compound 1 under n-BuLi alkaline condition and 3- methyl-3-butene-1-alcohol additions,
Compound 2, second step are obtained, the n-BuLi cyclization of compound 2 generates compound 3, third step, 3 ozonization of compound
Compound 4 is obtained, the 4th step obtains final compound 5 with sodium borohydride reduction carbonyls 4；Reaction equation is as follows：
Solvent in reaction equation is one kind in tetrahydrofuran, ethyl acetate, methanol, dichloromethane or water.
2. tertiary butyl -8- hydroxyls -5- oxa- -2- azaspiros [3.5] nonane -2- carboxylates according to claim 1
Synthetic method, it is characterized in that：First step solvent is tetrahydrofuran, and tetramethylethylenediamine is added in reaction.
3. tertiary butyl -8- hydroxyls -5- oxa- -2- azaspiros [3.5] nonane -2- carboxylates according to claim 1
Synthetic method, characterized in that it is methanol that third, which walks reaction dissolvent,.
4. tertiary butyl -8- hydroxyls -5- oxa- -2- azaspiros [3.5] nonane -2- carboxylates according to claim 1
Synthetic method, characterized in that four-step reaction solvent is methanol, is reacted at room temperature 1 hour.
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| CN107383038A (en) * | 2017-06-29 | 2017-11-24 | 上海合全药物研发有限公司 | A kind of synthetic method of the t-butyl formate of 8 oxygen subunit, 5 oxa-, 2 azaspiro [3.5] nonane 2 |
| CN109503579A (en) * | 2018-12-17 | 2019-03-22 | 天津药明康德新药开发有限公司 | The preparation method of tert-butyl -1- methyl -5- oxygen subunit thriazaspiro [5.5] hendecane -9- formic acid base ester |
| CN113214290B (en) * | 2021-04-13 | 2022-04-19 | 南通药明康德医药科技有限公司 | Synthesis method of 2, 5-dioxa-8-azaspiro [3.5] nonane and salt thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017268A (en) * | 2014-04-16 | 2015-11-04 | 上海药明康德新药开发有限公司 | 2-tertbutyloxycarbonyl-7-carbonyl-5-O-2-azaspiro(3.4)octane synthesis method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017268A (en) * | 2014-04-16 | 2015-11-04 | 上海药明康德新药开发有限公司 | 2-tertbutyloxycarbonyl-7-carbonyl-5-O-2-azaspiro(3.4)octane synthesis method |
Non-Patent Citations (2)
| Title |
|---|
| Spirocyclic amino alcohol building blocks prepared via a Prins-type cyclization in aqueous sulfuric acid;Alexey Lukin,et al.,;《Tetrahedron Letters》;20160616;第57卷;第3313-3314页 * |
| Synthesis of oxaspiropiperidines as a strategy for lowering logD;Timothy Cernak,et al.,;《Tetrahedron Letters》;20110925;第52卷;第6457–6459页 * |
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