CN108440494A - A kind of synthetic method of (S)-N- t-butyl formate -3- amino thiophanes of convenience and high-efficiency - Google Patents
A kind of synthetic method of (S)-N- t-butyl formate -3- amino thiophanes of convenience and high-efficiency Download PDFInfo
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- CN108440494A CN108440494A CN201810565489.5A CN201810565489A CN108440494A CN 108440494 A CN108440494 A CN 108440494A CN 201810565489 A CN201810565489 A CN 201810565489A CN 108440494 A CN108440494 A CN 108440494A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
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Abstract
The present invention relates to pharmaceutical chemistry technical field, more particularly to the synthetic method of the 3 amino thiophane of (S) N t-butyl formates of a kind of convenience and high-efficiency.The synthetic method of 3 amino thiophane of (S) N t-butyl formates provided by the invention is using (R) 2 aminosuccinic acid cheap and easy to get as raw material; amount to the reaction of five steps by esterification, amido protecting, reduction, sulfonation, cyclization; total recovery has up to 86% and reacts simple, low-cost good result.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, more particularly to (S)-N- t-butyl formates -3- of a kind of convenience and high-efficiency
The synthetic method of amino thiophane.
Background technology
(S)-N- t-butyl formates -3- amino thiophanes are a kind of widely used chemical intermediates, can be synthesized more
The intermediate of kind Medicine, pesticide, Polymer Synthesizing auxiliary agent has important application in medicine with Chemical Manufacture.
It is disclosed in patent WO2018004290 and has synthesized a kind of novel anti-cancer agent, this new drug is that a kind of pyrazoles spread out
Biology, structure is as shown in compound 1, the molecule fragment containing amino thiophane in molecular structure.
Martin et al. is open in 2017 to have synthesized a kind of steroidal anti-inflammatory drugs, is successfully applied to inflammatory reaction and itself
The treatment of immunity disease, such as asthma, chronic obstructive pulmonary disease, high fever and each anaphylactoid reaction.Its structure such as chemical combination
Shown in object 2, the molecule fragment in structure also containing amino thiophane.(Martin et al Journal of Medical
Chemistry,2017,60(20):8591-8605).
With the development of science and technology many new application fields are being continually developed out, domestic potential demand amount is very big.But mesh
It is preceding that there has been no reliable synthetic route reports.Therefore, low, easy to operate, high conversion rate generation (the S)-N- of development cost is explored
The method of t-butyl formate -3- amino thiophanes, either in terms of basic research, or in actual production application side
Face all has important researching value.
Invention content
The purpose of the present invention is to provide a kind of conjunctions of (S)-N- t-butyl formate -3- amino thiophanes of convenience and high-efficiency
At method, using (R) -2- aminosuccinic acids as primary raw material, by following five steps simple reaction, target product is synthesized.
In the first aspect of the present invention, a kind of (S)-N- t-butyl formate -3- amino tetrahydrochysene thiophenes of convenience and high-efficiency are provided
The synthetic method of pheno comprising following steps：
A. with ethyl alcohol esterification occurs for (R) -2- aminosuccinic acids, and (R) -2- aminosuccinic acid diethylesters are prepared；
B. (R) -2- aminosuccinic acids diethylester reacts in the presence of base with protection reagent di-tert-butyl dicarbonate, obtains
(R) -2- ((tert-butoxycarbonyl) amino) diethyl succinate；
C. with sodium borohydride reduction reaction occurs for (R) -2- ((tert-butoxycarbonyl) amino) diethyl succinates, obtains
(R)-(1,4- dihydroxy butyl- 2- yls) t-butyl carbamate；
D. with methylsufonyl chloride sulfonating reaction occurs for (R)-(Isosorbide-5-Nitrae-dihydroxy butyl- 2- yls) t-butyl carbamate, obtains
(R) -2- ((tert-butoxycarbonyl) amino) butane -1,4- diyl dimethanesulfonates；
E. (R) -2- ((tert-butoxycarbonyl) amino) butane -1,4- diyls dimethanesulfonates and vulcanized sodium generation cyclization are anti-
It should obtain (S)-N- t-butyl formate -3- amino thiophanes.
Preferably, use sulfuric acid as catalyst in the step a.
Preferably, the molar ratio of (R) -2- aminosuccinic acids and ethyl alcohol is 1 in the step a：5~50；Ethyl alcohol and sulfuric acid
Volume ratio be 1:5~1:10.
Preferably, the alkali in the step b includes one in triethylamine, 4-dimethylaminopyridine, sodium carbonate or potassium carbonate
Kind is a variety of.
Preferably, the molar ratio of (R) -2- aminosuccinic acids diethylester, di-tert-butyl dicarbonate and alkali is in the step b
1:1~3：2~5；With 1,4- dioxane：H2O=2:1~3:1 is used as solvent.
Preferably, it after the completion of being reacted in the step b, removes solvent and aqueous citric acid solution (10%) is added until pH=
2, it is extracted with methyl tertiary butyl ether(MTBE), organic layer saturated common salt water washing, drying, reduced pressure, obtains (R) -2- ((tertiary fourth oxygen
Base carbonyl) amino) diethyl succinate.
Preferably, (R) -2- ((tert-butoxycarbonyl) amino) diethyl succinates and sodium borohydride in the step c
Molar ratio is 1:1~2.
Preferably, (R)-(Isosorbide-5-Nitrae-dihydroxy butyl- 2- yls) t-butyl carbamate and methylsufonyl chloride in the step d
Molar ratio is 1:3~4.
Preferably, in the step e (R) -2- ((tert-butoxycarbonyl) amino) butane-Isosorbide-5-Nitrae-diyl dimethanesulfonates with
The molar ratio of vulcanized sodium is 1:2~3.
Preferably, reaction temperature is 60~100 DEG C in the step e.
The beneficial effects of the invention are as follows：Using (R) -2- aminosuccinic acids cheap and easy to get as raw material, pass through esterification, amino
Protection, reduction, sulfonation, cyclization amount to the reaction of five steps, and total recovery is up to 86%.
Specific implementation mode
Illustrate technical scheme of the present invention below by way of specific embodiment, but the scope of the present invention is not limited thereto.
Embodiment 1
1) (R) -2- aminosuccinic acids 1.5g, 98% sulfuric acid are added in dry reaction bottle:Ethyl alcohol (1mL：10mL), 100
DEG C reflux 4 hours.After the completion of reaction, reaction solution is cooled to room temperature, is concentrated under reduced pressure, obtains 2.5g colourless oil liquids, i.e.,
(R) -2- aminosuccinic acids diethylester, yield 100%.This intermediate is directly used in and reacts in next step without purifying.
Embodiment 2
2.1) under conditions of 0 DEG C, (R) -2- aminosuccinic acid diethylester 2.5g, sodium carbonate are added in dry reaction bottle
2.8g, di-tert-butyl dicarbonate 3.02g, with Isosorbide-5-Nitrae-dioxane：H2O(7mL：3mL) solution stirs 12 at room temperature as solvent
Hour.After the completion of reaction, removes solvent and aqueous citric acid solution (10%) is added up to pH=2, extracted with methyl tertiary butyl ether(MTBE),
Organic layer saturated common salt water washing, uses Na2SO4It is dry, it is concentrated under reduced pressure, obtains 2.9g colourless oil liquids, i.e. (R) -2- ((uncles
Butoxy carbonyl) amino) diethyl succinate, yield 89%.
1H NMR(400MHz,CDCl3) δ (ppm) 5.42 (m, 1H), 4.49 (m, 1H), 4.05~4.17 (m, 4H), 2.75
(d, J=4.8Hz, 1H), 2.71 (d, J=4.8Hz, 1H), 1.38 (s, 9H), 1.12~1.22 (m, 6H)
2.2) under conditions of 0 DEG C, (R) -2- aminosuccinic acid diethylester 2.5g, triethylamine are added in dry reaction bottle
3mL and di-tert-butyl dicarbonate 3.02g, with Isosorbide-5-Nitrae-dioxane：H2O(7mL：3mL) solution stirs at room temperature as solvent
12 hours.After the completion of reaction, removes solvent and aqueous citric acid solution (10%) is added until pH=2, is extracted with methyl tertiary butyl ether(MTBE)
It takes, organic layer saturated common salt water washing uses Na2SO4It is dry, it is concentrated under reduced pressure, obtains 3g colourless oil liquids, i.e. (R) -2-
((tert-butoxycarbonyl) amino) diethyl succinate, yield 92%.1H NMR(400MHz,CDCl3)δ(ppm)5.42(m,
1H), 4.49 (m, 1H), 4.05~4.17 (m, 4H), 2.75 (d, J=4.8Hz, 1H), 2.71 (d, J=4.8Hz, 1H), 1.38
(s, 9H), 1.12~1.22 (m, 6H)
Embodiment 3
3.1) by (R) -2- ((tert-butoxycarbonyl) amino) diethyl succinate 2.5g, 20mL ethanol solutions are dissolved in
In, it is slowly added to sodium borohydride 0.33g, control temperature is less than 50 DEG C, is stirred at room temperature 2 hours.After the reaction was complete, it will react
Liquid pours into 30mL saturated salt solutions, filters and concentrates the filtrate to 20mL, extracted with methyl tertiary butyl ether(MTBE), organic layer is used full
And brine It, use Na2SO4It is dry, it is concentrated under reduced pressure, obtains oily liquids 1.5g, i.e. (R)-(Isosorbide-5-Nitrae-dihydroxy butyl- 2- yls)
T-butyl carbamate, yield 86%.
1H NMR (400MHz, DMSO) δ (ppm) 6.48 (d, J=8.8Hz, 1H), 4.60 (t, J=5.6Hz, 1H), 4.38
(t, J=5.2Hz, 1H), 3.24~3.47 (m, 4H), 2.52 (m, 1H), 1.66 (m, 1H), 1.42 (t, J=6.0Hz, 11H)
3.2) by (R) -2- ((tert-butoxycarbonyl) amino) diethyl succinate 2.5g, 20mL ethanol solutions are dissolved in
In, it is slowly added to sodium borohydride 0.49g, control temperature is less than 50 DEG C, is stirred at room temperature 2 hours.After the reaction was complete, it will react
Liquid pours into 30mL saturated salt solutions, filters and concentrates the filtrate to 20mL, extracted with methyl tertiary butyl ether(MTBE), organic layer is used full
And brine It, use Na2SO4It is dry, it is concentrated under reduced pressure, obtains oily liquids 1.6g, i.e. (R)-(Isosorbide-5-Nitrae-dihydroxy butyl- 2- yls)
T-butyl carbamate, yield 91%.
1H NMR (400MHz, DMSO) δ (ppm) 6.48 (d, J=8.8Hz, 1H), 4.60 (t, J=5.6Hz, 1H), 4.38
(t, J=5.2Hz, 1H), 3.24~3.47 (m, 4H), 2.52 (m, 1H), 1.66 (m, 1H), 1.42 (t, J=6.0Hz, 11H)
Embodiment 4
4.1) into dichloromethane (20mL) solution of 1.5g (R)-(1,4- dihydroxy butyl- 2- yls) t-butyl carbamate
3.1g triethylamines are added, 3.5g methylsufonyl chlorides are added dropwise at 0 DEG C for then temperature control, are stirred at room temperature 20 hours.It has reacted
Cheng Hou pours into reaction solution in 15mL water, detaches organic layer, saturated common salt water washing is used in combination, uses Na2SO4It dries and depressurizes dense
Contracting, obtains crude product, it is stirred 10 hours in 20mL petroleum ethers, is then filtered, 3.8g (R) -2- ((tert-butoxies are obtained
Carbonyl) amino) butane-Isosorbide-5-Nitrae-diyl dimethanesulfonate, yield 89%.1H NMR(400MHz,CDCl3)δ(ppm)4.72(d,J
=8.0Hz, 1H), 4.18~4.29 (m, 4H), 4.00 (d, J=4.4Hz, 1H), 2.98 (d, J=3.6Hz, 6H), 1.91~
2.01(m,2H),1.38(s,9H).
4.2) into dichloromethane (20mL) solution of 1.5g (R)-(1,4- dihydroxy butyl- 2- yls) t-butyl carbamate
3.1g triethylamines are added, 2.6g methylsufonyl chlorides are added dropwise at 0 DEG C for then temperature control, are stirred at room temperature 20 hours.It has reacted
Cheng Hou pours into reaction solution in 15mL water, detaches organic layer, saturated common salt water washing is used in combination, uses Na2SO4It dries and depressurizes dense
Contracting, obtains crude product, it is stirred 10 hours in 20mL petroleum ethers, is then filtered, 4g (R) -2- ((tert-butoxy carbonyls are obtained
Base) amino) butane-Isosorbide-5-Nitrae-diyl dimethanesulfonate, yield 93%.1H NMR(400MHz,CDCl3) δ (ppm) 4.72 (d, J=
8.0Hz, 1H), 4.18~4.29 (m, 4H), 4.00 (d, J=4.4Hz, 1H), 2.98 (d, J=3.6Hz, 6H), 1.91~2.01
(m,2H),1.38(s,9H).
Embodiment 5
5.1) to (R) -2- ((tert-butoxycarbonyl) amino) butane -1,4- diyl dimethanesulfonate 1.9g in dimethyl Asia
Na is added in solution in sulfone (20mL)2S·9H2O (2.5g) stirs mixture 2 hours at 60 DEG C.It, will after the completion of reaction
Reaction solution is poured into water, and is extracted with ethyl acetate, and organic layer saturated common salt water washing uses Na2SO4It is dry, it is concentrated under reduced pressure, uses
Petroleum ether washes solid product, obtains 0.64g yellow solids, i.e. (S)-N- t-butyl formates -3- amino thiophanes, yield
80%.1H NMR(400MHz,CDCl3) δ (ppm) 4.68 (s, 1H), 4.35 (s, 1H), 2.85~3.00 (m, 1H), 2.77~
2.85 (m, 2H), 2.60~2.63 (m, 1H), 1.90~1.99 (m, 2H), 1.38 (s, 9H)
5.2) to (R) -2- ((tert-butoxycarbonyl) amino) butane -1,4- diyl dimethanesulfonate 1.9g in dimethyl Asia
Na is added in solution in sulfone (20mL)2S·9H2O (3.8g) stirs mixture 2 hours at 100 DEG C.After the completion of reaction,
Reaction solution is poured into water, is extracted with ethyl acetate, organic layer saturated common salt water washing uses Na2SO4It is dry, it is concentrated under reduced pressure,
Solid product is washed with petroleum ether, obtains 0.7g yellow solids, is i.e. (S)-N- t-butyl formates -3- amino thiophanes, yield
86%.1H NMR(400MHz,CDCl3) δ (ppm) 4.68 (s, 1H), 4.35 (s, 1H), 2.85~3.00 (m, 1H), 2.77~
2.85 (m, 2H), 2.60~2.63 (m, 1H), 1.90~1.99 (m, 2H), 1.38 (s, 9H).
It is enlightenment with above-mentioned desirable embodiment according to the present invention, through the above description, relevant staff is complete
Various changes and amendments can be carried out without departing from the scope of the technological thought of the present invention' entirely.The technology of this invention
Property range is not limited to the contents of the specification, it is necessary to determine its technical scope according to right.
Claims (10)
1. a kind of synthetic method of (S)-N- t-butyl formate -3- amino thiophanes of convenience and high-efficiency, it is characterised in that including
Following steps：
A. with ethyl alcohol esterification occurs for (R) -2- aminosuccinic acids, and (R) -2- aminosuccinic acid diethylesters are prepared；
B. (R) -2- aminosuccinic acids diethylester reacts in the presence of base with protection reagent di-tert-butyl dicarbonate, obtains (R) -
2- ((tert-butoxycarbonyl) amino) diethyl succinate；
C. with sodium borohydride reduction reaction occurs for (R) -2- ((tert-butoxycarbonyl) amino) diethyl succinates, obtains (R) -
(1,4- dihydroxy butyl- 2- yls) t-butyl carbamate；
D. with methylsufonyl chloride sulfonating reaction occurs for (R)-(Isosorbide-5-Nitrae-dihydroxy butyl- 2- yls) t-butyl carbamate, obtains (R)-
2- ((tert-butoxycarbonyl) amino) butane -1,4- diyl dimethanesulfonates；
E. (R) -2- ((tert-butoxycarbonyl) amino) butane -1,4- diyls dimethanesulfonates are obtained with vulcanized sodium generation ring-closure reaction
To (S)-N- t-butyl formate -3- amino thiophanes.
2. the synthetic method of (S)-N- t-butyl formate -3- amino thiophanes as described in claim 1, which is characterized in that
Use sulfuric acid as catalyst in the step a.
3. the synthetic method of (S)-N- t-butyl formate -3- amino thiophanes as described in claim 1, which is characterized in that
The molar ratio of (R) -2- aminosuccinic acids and ethyl alcohol is 1 in the step a：5~50；The volume ratio of ethyl alcohol and sulfuric acid is 1:5~
1:10。
4. the synthetic method of (S)-N- t-butyl formate -3- amino thiophanes as described in claim 1, which is characterized in that
Alkali in the step b includes one or more in triethylamine, 4-dimethylaminopyridine, sodium carbonate or potassium carbonate.
5. the synthetic method of (S)-N- t-butyl formate -3- amino thiophanes as described in claim 1, which is characterized in that
The molar ratio of (R) -2- aminosuccinic acids diethylester, di-tert-butyl dicarbonate and alkali is 1 in the step b:1~3：2~5；With
1,4- dioxane：H2O=2:1~3:1 is used as solvent.
6. the synthetic method of (S)-N- t-butyl formate -3- amino thiophanes as described in claim 4 or 5, feature exist
In after the completion of being reacted in step b described in the step, simultaneously aqueous citric acid solution is added until pH=2, uses methyl- tert in removing solvent
Butyl ether extracts, and organic layer saturated common salt water washing, drying, reduced pressure obtain (R) -2- ((tert-butoxycarbonyl) ammonia
Base) diethyl succinate.
7. the synthetic method of (S)-N- t-butyl formate -3- amino thiophanes as described in claim 1, which is characterized in that
The molar ratio of (R) -2- ((tert-butoxycarbonyl) amino) diethyl succinates and sodium borohydride is 1 in the step c:1~2.
8. the synthetic method of (S)-N- t-butyl formate -3- amino thiophanes as described in claim 1, which is characterized in that
The molar ratio of (R)-(1,4- dihydroxy butyl- 2- yls) t-butyl carbamate and methylsufonyl chloride is 1 in the step d:3~4.
9. the synthetic method of (S)-N- t-butyl formate -3- amino thiophanes as described in claim 1, which is characterized in that
The molar ratio of (R) -2- ((tert-butoxycarbonyl) amino) butane -1,4- diyls dimethanesulfonate and vulcanized sodium in the step e
It is 1:2~3.
10. the synthetic method of (S)-N- t-butyl formate -3- amino thiophanes as described in claim 1, which is characterized in that
Reaction temperature is 60~100 DEG C in the step e.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107540575A (en) * | 2017-10-13 | 2018-01-05 | 和鼎（南京）医药技术有限公司 | A kind of preparation method of sitagliptin intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107540575A (en) * | 2017-10-13 | 2018-01-05 | 和鼎（南京）医药技术有限公司 | A kind of preparation method of sitagliptin intermediate |
Non-Patent Citations (1)
| Title |
|---|
| ERNEST W. DELLA等: "《The Regiochemistry of Cyclization of r-Sulfenyl-, r-Sulfinyl-, andr-Sulfonyl-5-hexenyl Radicals: Procedures Leading toRegioselective Syntheses of Cyclic Sulfones and Sulfoxides》", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
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Application publication date: 20180824 |