CN103408511A - Method for synthesizing 3-heterocyclic amino oxygen butane-3-formic acid - Google Patents
Method for synthesizing 3-heterocyclic amino oxygen butane-3-formic acid Download PDFInfo
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- CN103408511A CN103408511A CN2013103957316A CN201310395731A CN103408511A CN 103408511 A CN103408511 A CN 103408511A CN 2013103957316 A CN2013103957316 A CN 2013103957316A CN 201310395731 A CN201310395731 A CN 201310395731A CN 103408511 A CN103408511 A CN 103408511A
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- ISLNOBFNRJECCG-UHFFFAOYSA-N CC(C)C1OCC1(C(O)=O)N Chemical compound CC(C)C1OCC1(C(O)=O)N ISLNOBFNRJECCG-UHFFFAOYSA-N 0.000 description 1
- CAVRRCLYIQHGKZ-UHFFFAOYSA-N N#CC1(COC1)NCc1cccc(C/[O]=C(\C2(COC2)NCc2ccccc2)/O)c1 Chemical compound N#CC1(COC1)NCc1cccc(C/[O]=C(\C2(COC2)NCc2ccccc2)/O)c1 CAVRRCLYIQHGKZ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a new method for synthesizing 3-heterocyclic amino oxygen butane-3-formic acid. The method comprises the following steps: performing protection and hydrolysis reaction on 3-oxetanone serving as an initial raw material to obtain a key intermediate to ensure that the yield is more than 70 percent; and performing debenzylation to obtain 3-heterocyclic amino oxygen butane-3-formic acid to ensure that the total yield is more than 60 percent. All kinds of adverse factors of 3-heterocyclic amino oxygen butane-3-formic acid on amplified production can be overcome, and the method has the advantages of low cost of raw materials, short routines, application of hazard-free reagents, high yield and the like, so that the product can be produced in a scaled mode, and is low in cost and convenient to popularize.
Description
Technical field
The present invention relates to biomedicine field, especially relate to a kind of synthetic method of pharmaceutical intermediate.
Background technology
3-is amino, and trimethylene oxide-3-formic acid is important biological medicine intermediate, can be widely used in the middle of various medicines synthetic.Its molecular weight is little, and the structure uniqueness can derive multiple derived product, just has been widely used.At present, the method for synthetic this compound does not also have bibliographical information, has seriously hindered exploitation and its further developing at biomedicine field of its derived product.
Summary of the invention
Technical problem solved by the invention is to provide the method for the amino trimethylene oxide of a kind of synthetic 3-newly-3-formic acid; it can overcome the amino trimethylene oxide of 3--3-formic acid in all unfavorable factors of amplifying on producing; and have that raw material is cheap, route is short, the use without hazardous agents, yield high; make this product can carry out the mass-producing generation; and cheap, be convenient to promote.
The technical scheme that its technical problem that solves this patent adopts is: the 3-oxetanone of take is starting raw material, and protection on process obtains key intermediate after hydrolysis reaction; yield is greater than 70%; then de-benzyl obtains the amino trimethylene oxide of 3--3-formic acid, and total recovery is greater than 60%, and route is as follows:
Concrete steps can be:
(1) upper protective reaction:
The 3-oxetanone is dissolved in anhydrous methylene chloride, adds benzylamine, stirring at room 1 hour, be cooled to 0 ℃, slowly adds cuprous cyanide, and under room temperature, reaction is 6 hours, and the TLC detection reaction is complete; Reaction solution is poured in separating funnel, water washing, the saturated sodium-chloride washing, anhydrous sodium sulfate drying, be spin-dried for solvent, and column chromatography obtains product 2;
(2) hydrolysis reaction:
Compound 2 is dissolved in methyl alcohol, stirs, add the aqueous solution of sodium hydroxide, reflux, reacted 8 hours, and the TLC detection reaction is complete; Reaction solution is poured in separating funnel, and the methyl tertiary butyl ether extracting impurities, then be adjusted to neutrality with the hydrochloric acid of 1mol/L by reaction solution, water drawn dry with oil pump, and column chromatography obtains product 3;
(3) debenzylation reaction:
Compound 3 is dissolved in anhydrous methanol, stirs, add palladium carbon, install hydrogenation apparatus, replacing hydrogen three times, regulate force value to 40Psi, reacts after 2 hours, and the TLC detection reaction is complete; By reacting liquid filtering, be spin-dried for filtrate, column chromatography obtains product 4.
The beneficial effect of this patent is, avoided hazardous chemical use, reduced reaction cost, improved reaction yield, simple to operate, easily purifying, can amplify production.This patent adopts conventional operation process; the comparatively cheap raw material of the 3-oxetanone of usining is as initial reactant; after upper protection, hydrolysis, debenzylation reaction, obtain final product; avoided the use of dangerous raw material; avoided complicated purification process operation; and higher reaction yield is arranged, make the amplification of this compound easily realize.Method of the present invention is through upper protection, hydrolysis, debenzylation reaction, and synthetic route is short, high without use, the yield of hazardous agents, makes the product made can carry out the mass-producing generation, and cheap, is convenient to promote.And purifying is simple and convenient, reduced the cost of suitability for industrialized production, solved the shortcoming of amplifying the production cost costliness.
Embodiment
For further illustrating the present invention, illustrate with the following Examples:
Embodiment 1: laboratory is synthetic
1. go up protective reaction
3-oxetanone (10g) is dissolved in anhydrous methylene chloride (100mL), adds benzylamine (22.5g), stirring at room 1 hour, be cooled to 0 ℃, slowly adds cuprous cyanide (20.6g), and under room temperature, reaction is 6 hours, and the TLC detection reaction is complete.Reaction solution is poured in separating funnel, water washing, the saturated sodium-chloride washing, anhydrous sodium sulfate drying, be spin-dried for solvent, column chromatography obtains product 2(23g), yield is 88%.
2. hydrolysis reaction
By compound 2(10g) be dissolved in the mixed solution of methyl alcohol (140mL), stir, add the aqueous solution of sodium hydroxide (4.3g, 2mol/L), reflux, reacted 8 hours, and the TLC detection reaction is complete.Reaction solution is poured in separating funnel, and the methyl tertiary butyl ether extracting impurities, then be adjusted to neutrality with the hydrochloric acid of 1mol/L by reaction solution, water drawn dry with oil pump, and column chromatography obtains product 3(9.4g), yield is 85%.
3. debenzylation reaction
By compound 3(10g) be dissolved in anhydrous methanol (100mL), stir, add palladium carbon (1g), install hydrogenation apparatus, replacing hydrogen three times, regulate force value to 40Psi, reacts after 2 hours, and the TLC detection reaction is complete.By reacting liquid filtering, be spin-dried for filtrate, column chromatography obtains product 4(5.3g), yield is 94%.
Embodiment 2: lab scale
1. go up protective reaction
3-oxetanone (100g) is dissolved in anhydrous methylene chloride (1L), adds benzylamine (225g), stirring at room 1 hour, be cooled to 0 ℃, slowly adds cuprous cyanide (206g), and under room temperature, reaction is 6 hours, and the TLC detection reaction is complete.Reaction solution is poured in separating funnel, water washing, the saturated sodium-chloride washing, anhydrous sodium sulfate drying, be spin-dried for solvent, column chromatography obtains product 2(230g), yield is 88%.
2. hydrolysis reaction
By compound 2(100g) be dissolved in the mixed solution of methyl alcohol (1.4L), stir, add the aqueous solution of sodium hydroxide (43g, 2mol/L), reflux, reacted 8 hours, and the TLC detection reaction is complete.Reaction solution is poured in separating funnel, and the methyl tertiary butyl ether extracting impurities, then be adjusted to neutrality with the hydrochloric acid of 1mol/L by reaction solution, water drawn dry with oil pump, and column chromatography obtains product 3(94g), yield is 85%.
3. debenzylation reaction
By compound 3(100g) be dissolved in anhydrous methanol (1L), stir, add palladium carbon (10g), install hydrogenation apparatus, replacing hydrogen three times, regulate force value to 40Psi, reacts after 2 hours, and the TLC detection reaction is complete.By reacting liquid filtering, be spin-dried for filtrate, column chromatography obtains product 4(53g), yield is 94%.
Embodiment 3: pilot scale
1. go up protective reaction
3-oxetanone (1kg) is dissolved in anhydrous methylene chloride (10L), adds benzylamine (2.25kg), stirring at room 1 hour, be cooled to 0 ℃, slowly adds cuprous cyanide (2.06kg), and under room temperature, reaction is 6 hours, and the TLC detection reaction is complete.Reaction solution is poured in separating funnel, water washing, the saturated sodium-chloride washing, anhydrous sodium sulfate drying, be spin-dried for solvent, column chromatography obtains product 2(22.3kg), yield is 88%.
2. hydrolysis reaction
By compound 2(1kg) be dissolved in the mixed solution of methyl alcohol (14L), stir, add the aqueous solution of sodium hydroxide (430g, 2mol/L), reflux, reacted 8 hours, and the TLC detection reaction is complete.Reaction solution is poured in separating funnel, and the methyl tertiary butyl ether extracting impurities, then be adjusted to neutrality with the hydrochloric acid of 1mol/L by reaction solution, water drawn dry with oil pump, and column chromatography obtains product 3(940g), yield is 85%.
3. debenzylation reaction
By compound 3(1kg) be dissolved in anhydrous methanol (10L), stir, add palladium carbon (100g), install hydrogenation apparatus, replacing hydrogen three times, regulate force value to 40Psi, reacts after 2 hours, and the TLC detection reaction is complete.By reacting liquid filtering, be spin-dried for filtrate, column chromatography obtains product 4(530g), yield is 94%.
As can be seen from the above embodiments, synthetic method of the present invention can directly be amplified, for industrial production.This patent adopts conventional operation process; the comparatively cheap raw material of the 3-oxetanone of usining is as initial reactant; after upper protection, hydrolysis, debenzylation reaction, obtain final product; avoided the use of dangerous raw material; avoided complicated purification process operation; and higher reaction yield is arranged, make the amplification of this compound easily realize.Method of the present invention is through upper protection, hydrolysis, debenzylation reaction, and synthetic route is short, high without use, the yield of hazardous agents, makes the product made can carry out the mass-producing generation, and cheap, is convenient to promote.And purifying is simple and convenient, reduced the cost of suitability for industrialized production, solved the shortcoming of amplifying the production cost costliness.
Above-described embodiment is described the preferred embodiment of the present invention; not scope of the present invention is limited; design under the prerequisite of spirit not breaking away from the present invention; various distortion and improvement that the common engineering technical personnel in this area make technical scheme of the present invention, all should fall in the definite protection domain of claims of the present invention.
Claims (3)
1. the method for the amino trimethylene oxide of synthetic 3--3-formic acid; it is characterized in that: the 3-oxetanone of take is starting raw material, obtains key intermediate after upper protection, hydrolysis reaction, and yield is greater than 70%; then de-benzyl obtains the amino trimethylene oxide of 3--3-formic acid, and total recovery is greater than 60%.
2. method according to claim 1, it is characterized in that: the process of described reaction is:
3. method according to claim 2, it is characterized in that: concrete steps are:
(1) upper protective reaction:
The 3-oxetanone is dissolved in anhydrous methylene chloride, adds benzylamine, stirring at room 1 hour, be cooled to 0 ℃, slowly adds cuprous cyanide, and under room temperature, reaction is 6 hours, and the TLC detection reaction is complete; Reaction solution is poured in separating funnel, water washing, the saturated sodium-chloride washing, anhydrous sodium sulfate drying, be spin-dried for solvent, and column chromatography obtains product 2;
(2) hydrolysis reaction:
Compound 2 is dissolved in methyl alcohol, stirs, add the aqueous solution of sodium hydroxide, reflux, reacted 8 hours, and the TLC detection reaction is complete; Reaction solution is poured in separating funnel, and the methyl tertiary butyl ether extracting impurities, then be adjusted to neutrality with the hydrochloric acid of 1mol/L by reaction solution, water drawn dry with oil pump, and column chromatography obtains product 3;
(3) debenzylation reaction:
Compound 3 is dissolved in anhydrous methanol, stirs, add palladium carbon, install hydrogenation apparatus, replacing hydrogen three times, regulate force value to 40Psi, reacts after 2 hours, and the TLC detection reaction is complete; By reacting liquid filtering, be spin-dried for filtrate, column chromatography obtains product 4.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109988126A (en) * | 2017-12-29 | 2019-07-09 | 南京富润凯德生物医药有限公司 | A kind of 3- amino-oxetane derivative and its preparation method and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3449369A (en) * | 1965-11-22 | 1969-06-10 | Du Pont | Oxetane derivatives |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3449369A (en) * | 1965-11-22 | 1969-06-10 | Du Pont | Oxetane derivatives |
Non-Patent Citations (3)
| Title |
|---|
| ALAN P. KOZIKOWSKI ET AL.: "Synthesis of Novel Four-Membered Ring Amino Acids as Modulators of the N-Methyl-D-Aspartate(NMDA) Receptor Complex", 《SYNLETT》, vol. 11, 31 December 1991 (1991-12-31), pages 783 - 784 * |
| JOHANNES A. BURKHARD ET AL.: "Oxetanes as Versatile Elements in Drug Discovery and Synthesis", 《ANGEW. CHEM. INT. ED》, vol. 49, 31 December 2010 (2010-12-31), pages 9052 - 9067 * |
| YVES DEJAEGHER ET AL.: "The Chemistry of Azetidin-3-ones, Oxetan-3-ones, and Thietan-3-ones", 《CHEM. REV.》, vol. 102, 18 December 2001 (2001-12-18), pages 29 - 60 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109988126A (en) * | 2017-12-29 | 2019-07-09 | 南京富润凯德生物医药有限公司 | A kind of 3- amino-oxetane derivative and its preparation method and application |
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Application publication date: 20131127 |