CN106831818A - A kind of preparation method of the dicarboxylic acids of 2 tert-butyl group, 7 methyl, 5 oxa-, 2,8 diazaspiroalkanes [3,5] nonane 2,7 - Google Patents
A kind of preparation method of the dicarboxylic acids of 2 tert-butyl group, 7 methyl, 5 oxa-, 2,8 diazaspiroalkanes [3,5] nonane 2,7 Download PDFInfo
- Publication number
- CN106831818A CN106831818A CN201710068218.4A CN201710068218A CN106831818A CN 106831818 A CN106831818 A CN 106831818A CN 201710068218 A CN201710068218 A CN 201710068218A CN 106831818 A CN106831818 A CN 106831818A
- Authority
- CN
- China
- Prior art keywords
- compound
- methyl
- tert
- nonane
- oxa
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation method of the dicarboxylic acids of 2 tert-butyl group, 7 methyl, 5 oxa-, 2,8 diazaspiroalkanes [3,5] nonane 2,7, the technical problem currently without suitable Industrialized synthesis method is mainly solved.The present invention is divided into four steps：Compound 1 reacts in tetrahydrofuran and obtains compound 2 with n-BuLi and benzyl chloroformate first, then compound 3 is obtained with diphenyl phosphate chloride and potassium hexamethyldisilazide reaction, compound 3 is in the presence of CO, in the presence of palladium and triphenylphosphine, slotting carbonyl obtains compound 4, then in the presence of hydrogen and palladium carbon, hydro-reduction obtains target product compound 5 again.
Description
Technical field
The present invention relates to the 2- tert-butyl group -7- methyl -5- oxa- -2,8- diazaspiroalkanes-[3,5] nonane -2,7- dicarboxylic acids
Synthetic method.
Background technology
The 2- tert-butyl group -7- methyl -5- oxa- -2,8- diazaspiroalkanes-[3,5] nonane -2,7- dicarboxylic acids and correlation are spread out
Biology has extensive use in pharmaceutical chemistry and organic synthesis.At present on the 2- tert-butyl group -7- methyl -5- oxa- -2,8- bis-
Aza spiro alkane-[3,5] nonane -2, also without document report, there is certain danger in similar document reaction for the synthesis of 7- dicarboxylic acids
Property and route is long, yield is relatively low.Accordingly, it would be desirable to develop a raw material be easy to get, it is easy to operate, react easily controllable, overall yield
Suitable synthetic method.
The content of the invention
The purpose of the present invention is that exploitation one kind is easy to get with raw material, easy to operate, reacts easily controllable, yield 2- higher
The tert-butyl group -7- methyl -5- oxa- -2,8- diazaspiroalkanes-[3,5] nonane -2, the synthetic method of 7- dicarboxylic acids.Mainly solve mesh
The preceding technical problem without suitable Industrialized synthesis method.
Technical scheme：A kind of 2- tert-butyl groups -7- methyl -5- oxa- -2,8- diazaspiroalkanes-[3,5] nonane -
The preparation method of 2,7- dicarboxylic acids, comprises the following steps, and the present invention divides four steps, the first step, compound 1 and n-BuLi and chloromethane
Acid benzyl ester (CbzCl) reaction in the tetrahydrofuran (THF) obtains compound 2, second step, compound 2 and diphenyl phosphate chloride and
Potassium hexamethyldisilazide (KHMDS) reaction obtains compound 3, the 3rd step, compound 3 in the presence of CO, through palladium [Pd
(OAc)2] and triphenylphosphine effect, slotting carbonyl obtains compound 4, the 4th step, compound 4 in the presence of hydrogen and palladium carbon, then
Secondary hydro-reduction obtains target product compound 5, and reaction equation is as follows：
In the reaction, first step reaction temperature is -78 DEG C to -50 DEG C, reaction time 3-6 hours；Second step reaction temperature for-
78 DEG C Dao -60 DEG C, reaction time 3-6 hours；Three-step reaction need to add methyl alcohol and triethylamine mixed solvent, and reaction temperature exists
45-65 DEG C, react 16-24 hours, carbon monoxide pressure is 15-35psi；Four-step reaction temperature reacts 3-5 at 35-55 DEG C
My god, Hydrogen Vapor Pressure is 35-55psi.
Beneficial effects of the present invention：The invention provides one kind synthesis 2- tert-butyl group -7- methyl -5- oxa- -2,8- phenodiazines
Miscellaneous spirane-[3,5] nonane -2, the method for 7- dicarboxylic acids, except the 2nd, 3 steps have used column chromatography purifying in whole piece route, other steps
It is rapid to all employ recrystallization or the purification process of soda acid, purification time is greatlyd save with consumption, in general, the method road
Line is short, and yield may be up to 16.9%, and reaction is easy to amplify, easy to operate, with industrial applications prospect.
Specific embodiment
Reaction equation of the present invention is as follows：
Embodiment 1：A, compound 1 (430g, 1.77mol) is dissolved in the tetrahydrofuran of 3L, under the protection of nitrogen,
Controlling reaction temperature is added dropwise n-BuLi (125g, 1.95mol) at -78 DEG C to -50 DEG C.After completion of dropwise addition, maintenance reaction temperature
Degree, continues to stir 1-2 hours.Benzyl chloroformate (322.8g, 1.86mol) is dissolved in the tetrahydrofuran of 1L, control reaction
Temperature is added drop-wise in reaction solution at -78 DEG C to -50 DEG C.After completion of dropwise addition, maintenance reaction temperature continues to stir 2-4 hours.
TLC (petrol ether/ethyl acetate volume ratio=2/1) display reactions terminate.Reaction solution is poured into saturated aqueous ammonium chloride (5L)
In, extracted with ethyl acetate (3L x 3).Merge organic phase, dried over sodium sulfate, filtering, vacuum distillation is concentrated to give thick product
Product.Crude product is recrystallized through tertiary fourth level methyl ether (1L).Solid obtains the compound 2 (600g) of white solid through filtration drying,
Yield 90%.
B, compound 2 (185g, 0.49mol) is dissolved in tetrahydrofuran (700mL), under nitrogen protection, control is anti-
Temperature is answered at -78 DEG C to -60 DEG C, tetrahydrofuran (1L) solution of potassium hexamethyldisilazide (147g, 0.74mol) is added drop-wise to
In.After stirring 1-2 hours, at that same temperature, the tetrahydrofuran of diphenyl phosphate chloride (209.8g, 0.74mol) is added dropwise
(300mL) solution.After completion of dropwise addition, identical reaction temperature is controlled, continue to react 2-4 hours.TLC (petrol ether/ethyl acetates
Volume ratio=2/1) show that reaction terminates.Reaction solution is poured into saturated aqueous ammonium chloride (1.5L).It is subsequently adding the tert-butyl group
Methyl ether (1L) and the mass percentage concentration 10%NaOH aqueous solution (800mL).Organic phase is separated through knockout, saturation is used
Dried over sodium sulfate after saline solution (1L) washing, filtering, vacuum distillation is concentrated to give crude product.Crude product is through column chromatography (oil
Ether/ethyl acetate volume ratio=10/1,5/1) purify the compound 3 (268g) for obtaining yellow oily, yield 89%.
C, by compound 3 (148g, 243mmol), palladium (13.6g, 60.8mmol) and triphenylphosphine (31.9g,
N 0.12mol) is suspended in, in N '-dimethyl formamide (1.4L), under the pressure of carbon monoxide (15-35psi), control reaction
Temperature is reacted 0.5-2 hours at 15-35 DEG C.Then to addition MeOH (311.7g, 9.73mol) and triethylamine in reaction system
(49.2g, 0.48mol).Under the pressure of carbon monoxide (15-35psi), controlling reaction temperature is reacted at 45-65 DEG C for reaction
16-24 hours.Reaction solution is poured into 2L water, is extracted with ethyl acetate (1L x 3).Merge organic phase, with saturated aqueous common salt (1L)
Washing, dried over sodium sulfate, filtering, vacuum distillation is concentrated to give crude product.Crude product is through column chromatography (petrol ether/ethyl acetate
Volume ratio=10/1,2/1) purify the compound 4 (82g) for obtaining yellow oily, yield 81%.
D, compound 4 (62g, 0.148mol) and palladium carbon (6.5g, aqueous between 10%-70%) are suspended in 800mL
Methyl alcohol in, under the pressure of hydrogen (35-55psi), controlling reaction temperature at 35-55 DEG C, react 3-5 days.TLC (petroleum ether/
Ethyl acetate volume ratio=2/1) show that reaction terminates.Reaction solution is filtered through diatomite layer, and filter cake methyl alcohol (100mL x 3) is washed
Wash.Merging filtrate, concentrates through vacuum distillation.Gained crude product is suspended in 1N HCl (800mL) and ethyl acetate (800mL).
Water is separated through knockout, is alkalized to pH between 7-9 with aqueous sodium carbonate, is extracted with ethyl acetate (500mL x3)
Take.Merge organic phase, dried over sodium sulfate, filtering, vacuum distillation is concentrated to give the compound 5 (34g) of colorless oil, yield
80%.
δ=3.94-3.92 (d, 1H), 3.85-3.75 (m, 8H), 3.50 (m, 1H), 3.14-3.11 (d, 1H), 2.91-
2.88 (d, 1H), 2.17 (br, 1H), 1.43 (s, 9H).
Embodiment 2：A, compound 1 (4300g, 17.7mol) is dissolved in the tetrahydrofuran of 25L, in the protection of nitrogen
Under, controlling reaction temperature is added dropwise n-BuLi (1250g, 19.5mol) at -78 DEG C to -50 DEG C.After completion of dropwise addition, maintenance reaction
Temperature, continues to stir 1-2 hours.Benzyl chloroformate (3228g, 18.6mol) is dissolved in the tetrahydrofuran of 5L, control reaction
Temperature is added drop-wise in reaction solution at -78 DEG C to -50 DEG C.After completion of dropwise addition, maintenance reaction temperature continues to stir 2-4 hours.
TLC (petrol ether/ethyl acetate volume ratio=2/1) display reactions terminate.Reaction solution is poured into saturated aqueous ammonium chloride (35L)
In, extracted with ethyl acetate (15L x 3).Merge organic phase, dried over sodium sulfate, filtering, vacuum distillation is concentrated to give thick product
Product.Crude product is recrystallized through tertiary fourth level methyl ether (6L).Solid obtains the compound 2 (6kg) of white solid through filtration drying, receives
Rate 90%.
B, compound 2 (1850g, 4.9mol) is dissolved in tetrahydrofuran (5L), under nitrogen protection, control reaction temperature
Degree is added drop-wise in the tetrahydrofuran of potassium hexamethyldisilazide (1470g, 7.4mol) (6L) solution at -78 DEG C to -60 DEG C.
After stirring 1-2 hours, at that same temperature, the tetrahydrofuran (2L) that diphenyl phosphate chloride (2098g, 7.4mol) is added dropwise is molten
Liquid.After completion of dropwise addition, identical reaction temperature is controlled, continue to react 2-4 hours.TLC (petrol ether/ethyl acetate volume ratio=
2/1) display reaction terminates.Reaction solution is poured into saturated aqueous ammonium chloride (8L).It is subsequently adding t-butyl methyl ether (5L)
With the mass percentage concentration 10%NaOH aqueous solution (4L).Organic phase is separated through knockout, with saturated aqueous common salt (2.5L)
Dried over sodium sulfate after washing, filtering, vacuum distillation is concentrated to give crude product.Crude product is through column chromatography (petroleum ether/acetic acid second
Ester volume ratio=10/1,5/1) purify the compound 3 (2680g) for obtaining yellow oily, yield 89%.
C, by compound 3 (1480g, 2.43mol), palladium (136g, 0.608mol) and triphenylphosphine (319g,
N 1.2mol) is suspended in, in N '-dimethyl formamide (10L), under the pressure of carbon monoxide (15-35psi), control reaction temperature
Degree reacts 0.5-2 hours at 15-35 DEG C.Then to addition MeOH (3117g, 97.3mol) and triethylamine in reaction system
(492g, 4.8mol).Under the pressure of carbon monoxide (15-35psi), controlling reaction temperature reacts 16- at 45-65 DEG C for reaction
24 hours.Reaction solution is poured into 10L water, is extracted with ethyl acetate (5L x 3).Merge organic phase, washed with saturated aqueous common salt (3L)
Wash, dried over sodium sulfate, filtering, vacuum distillation is concentrated to give crude product.Crude product is through column chromatography (petrol ether/ethyl acetate body
Product ratio=10/1,2/1) purify the compound 4 (820g) for obtaining yellow oily, yield 81%.
D, compound 4 (620g, 1.48mol) and palladium carbon (65g, aqueous between 10%-70%) are suspended in the first of 5L
In alcohol, under the pressure of hydrogen (35-55psi), controlling reaction temperature is reacted 3-5 days at 35-55 DEG C.TLC (petroleum ethers/acetic acid
Ethyl ester volume ratio=2/1) show that reaction terminates.Reaction solution is filtered through diatomite layer, and filter cake is washed with methyl alcohol (500mL x 3).
Merging filtrate, concentrates through vacuum distillation.Gained crude product is suspended in 1N HCl (5L) and ethyl acetate (5L).Water is mutually through a point liquid
Device is separated, and is alkalized to pH between 7-9 with aqueous sodium carbonate, is extracted with ethyl acetate (3L x 3).Merge organic phase,
Dried over sodium sulfate, filtering, vacuum distillation is concentrated to give the compound 5 (340g) of colorless oil, yield 80%.
δ=3.94-3.92 (d, 1H), 3.85-3.75 (m, 8H), 3.50 (m, 1H), 3.14-3.11 (d, 1H), 2.91-
2.88 (d, 1H), 2.17 (br, 1H), 1.43 (s, 9H).
Claims (5)
1. a kind of 2- tert-butyl groups -7- methyl -5- oxa- -2,8- diazaspiroalkanes-[3,5] nonane -2, the preparation side of 7- dicarboxylic acids
Method, it is characterized in that comprising the following steps, four steps of the present invention point, the first step, compound 1 is with n-BuLi and benzyl chloroformate four
Reaction obtains compound 2 in hydrogen furans, and second step, compound 2 reacts with diphenyl phosphate chloride and potassium hexamethyldisilazide
Obtain compound 3, the 3rd step, in the presence of CO, through the effect of palladium and triphenylphosphine, slotting carbonyl obtains compound to compound 3
4, the 4th step, in the presence of hydrogen and palladium carbon, hydro-reduction obtains target product compound 5 to compound 4 again, and reaction equation is such as
Under：
2. a kind of 2- tert-butyl groups -7- methyl -5- oxa- -2 according to claim 1,8- diazaspiroalkanes-[3,5] nonane -
The preparation method of 2,7- dicarboxylic acids, it is characterized in that first step reaction temperature is -78 DEG C to -50 DEG C, reaction time 3-6 hours.
3. a kind of 2- tert-butyl groups -7- methyl -5- oxa- -2 according to claim 1,8- diazaspiroalkanes-[3,5] nonane -
The preparation method of 2,7- dicarboxylic acids, it is characterized in that second step reaction temperature is -78 DEG C to -60 DEG C, reaction time 3-6 hours.
4. a kind of 2- tert-butyl groups -7- methyl -5- oxa- -2 according to claim 1,8- diazaspiroalkanes-[3,5] nonane -
The preparation method of 2,7- dicarboxylic acids, it is characterized in that three-step reaction need to add methyl alcohol and triethylamine mixed solvent, reaction temperature exists
45-65 DEG C, react 16-24 hours, carbon monoxide pressure is 15-35psi.
5. a kind of 2- tert-butyl groups -7- methyl -5- oxa- -2 according to claim 1,8- diazaspiroalkanes-[3,5] nonane -
The preparation method of 2,7- dicarboxylic acids, it is characterized in that four-step reaction temperature is at 35-55 DEG C, reacts 3-5 days, and Hydrogen Vapor Pressure is 35-
55psi。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710068218.4A CN106831818A (en) | 2017-02-07 | 2017-02-07 | A kind of preparation method of the dicarboxylic acids of 2 tert-butyl group, 7 methyl, 5 oxa-, 2,8 diazaspiroalkanes [3,5] nonane 2,7 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710068218.4A CN106831818A (en) | 2017-02-07 | 2017-02-07 | A kind of preparation method of the dicarboxylic acids of 2 tert-butyl group, 7 methyl, 5 oxa-, 2,8 diazaspiroalkanes [3,5] nonane 2,7 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106831818A true CN106831818A (en) | 2017-06-13 |
Family
ID=59122892
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710068218.4A Pending CN106831818A (en) | 2017-02-07 | 2017-02-07 | A kind of preparation method of the dicarboxylic acids of 2 tert-butyl group, 7 methyl, 5 oxa-, 2,8 diazaspiroalkanes [3,5] nonane 2,7 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106831818A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016020836A1 (en) * | 2014-08-06 | 2016-02-11 | Novartis Ag | Quinolone derivatives as antibacterials |
| WO2016042452A1 (en) * | 2014-09-16 | 2016-03-24 | Shire International Gmbh | Spirocyclic derivatives |
-
2017
- 2017-02-07 CN CN201710068218.4A patent/CN106831818A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016020836A1 (en) * | 2014-08-06 | 2016-02-11 | Novartis Ag | Quinolone derivatives as antibacterials |
| WO2016042452A1 (en) * | 2014-09-16 | 2016-03-24 | Shire International Gmbh | Spirocyclic derivatives |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2022222914A1 (en) | Preparation method of l-nicotine | |
| CN104487430A (en) | Process for making hydroxylated cyclopentylpyrimidine compounds | |
| CN101712645B (en) | Preparation method for (2R, 4R)-4-substituted-2-piperidine carboxylic acid compound and intermediate thereof | |
| CN102086222A (en) | Preparation method of beta-thymidine | |
| CN107383026B (en) | A kind of synthetic method of 7- methylol -2,5- diaza spiro [3,4] octane -2- t-butyl formate | |
| CN108863958A (en) | A kind of preparation method of 4,7- diaza spiro [2.5] Octane derivatives | |
| CN101563312A (en) | Process for producing intermediate of asenapine synthesis | |
| CN108912032A (en) | It is a kind of（3S, 4R）The chemical synthesis process of -4- methylpyrrolidin- 3- base amino methanol t-butyl ester hydrochloride | |
| CN106831818A (en) | A kind of preparation method of the dicarboxylic acids of 2 tert-butyl group, 7 methyl, 5 oxa-, 2,8 diazaspiroalkanes [3,5] nonane 2,7 | |
| CN110878099B (en) | Preparation method of pyrrole [1,2, alpha ] indole alkaloid derivative | |
| CN103788010B (en) | Febuxostat intermediate and preparation method thereof | |
| CN103965042B (en) | A kind of synthetic method of ethoxy ethyl acrylate | |
| CN105622538A (en) | One-pot high-yielding preparation of cetilistat | |
| CN107674016B (en) | Preparation method of telaprevir intermediate and intermediate thereof | |
| CN110981901A (en) | Purification method of amino-terminated siloxane | |
| CN103665084A (en) | Method for preparing abiraterone acetate | |
| CN107216332A (en) | The synthetic method of (6H) the formic acid base ester of 7 methylol of the tert-butyl group, 7,8 dihydro 4H pyrazolos diazepine 5 | |
| CN104987325B (en) | A kind of preparation method of voriconazole | |
| CN106632453A (en) | Preparation method for synthesizing key intermediate 4-BMA of 1beta-methyl carbapenem antibiotic bicyclic nucleus | |
| CN101979393A (en) | Method for synthesizing cephalothin acid by using 7-aminocephalosporanic acid (ACA) | |
| CN109721604A (en) | The preparation method of pemetrexed acid | |
| CN105017251B (en) | A kind of Preparation Method And Their Intermediate of nk 1 receptor antagonist | |
| CN104418735A (en) | Preparation method of adamantine monoester | |
| CN114213398B (en) | Preparation method of polysubstituted furan derivative, bactericide and application | |
| CN103992257B (en) | A kind of purification process of Vildagliptin crude product |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170613 |