CN105924369A - Preparation method of N-(t-butoxy carbonyl)-L-leucine-N'-methoxy-N'-methylformamide intermediate - Google Patents
Preparation method of N-(t-butoxy carbonyl)-L-leucine-N'-methoxy-N'-methylformamide intermediate Download PDFInfo
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- CN105924369A CN105924369A CN201510958434.7A CN201510958434A CN105924369A CN 105924369 A CN105924369 A CN 105924369A CN 201510958434 A CN201510958434 A CN 201510958434A CN 105924369 A CN105924369 A CN 105924369A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
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Abstract
The invention provides a preparation method of N-(t-butoxy carbonyl)-L-leucine-N'-methoxy-N'-methylformamide intermediate. The method includes the steps of: A) reacting a compound A and a compound B in dichloromethane under the action of a Carter condensation agent; B) concentrating to remove 20%-40% of the dichloromethane; C) adding a second solvent, extracting, concentrating the second solvent to obtain the N-(t-butoxycarbonyl)-L-leucine-N'-methoxy-N'-methylformamide intermediate, wherein the second solvent is one or more of petroleum ether, n-heptane, n-hexane, cyclohexane and octane, and in the extraction, the weight ratio of the second solvent to remaining dichloromethane after concentration is (0.6-0.9):1. The method uses two specific mutual solvents, which can be layered in specific proportion; and the impurities and the products in the reaction system are respectively dissolved in different solvents, thereby reaching the effects of separation and purification.
Description
Technical field
The present invention relates to technical agent field, particularly relate to a kind of N-(tert-butoxycarbonyl)-L-Leu-N'-methoxy
The preparation method of base-N'-methyl nitrosourea intermediate.
Background technology
Following compound is as the medicine preparing N-(tert-butoxycarbonyl)-L-Leu-N'-methoxyl group-N'-methyl nitrosourea
Thing key intermediate, market demand is the biggest.
Use acyl chlorides activation synthetic method more at present the preparation of above-claimed cpd, need a BOC-L-leucine (hydrate
Thing) be processed into anhydrous, and reaction condition control relatively harsh, environmental pollution is bigger.
Also have been reported that employing condensing agent activation synthetic method, add and block special condensing agent, the method mild condition, it can be difficult to will
The salt that condensing agent generates eliminates, and being also difficult to eliminate even if repeatedly washing in dichloromethane, leveraging product yield on the contrary,
And product is that grease and viscosity are very big, needs column chromatography to reach purification effect.Industry is difficult to amplify production.
Summary of the invention
In view of this, the technical problem to be solved in the present invention be to provide a kind of N-(tert-butoxycarbonyl)-L-Leu-
The preparation method of N'-methoxyl group-N'-methyl nitrosourea intermediate, post processing is simple, is suitable for amplifying production.
The invention provides a kind of N-(tert-butoxycarbonyl)-L-Leu-N'-methoxyl group-N'-methyl nitrosourea intermediate
Preparation method, including:
A) by compound A, compound B under the effect of the special condensing agent of card, react in dichloromethane；
B) dichloromethane of removing 20%～40% is concentrated；
C) add the second solvent to extract, the second solvent phase be concentrated to give N-(tert-butoxycarbonyl)-L-Leu-
N'-methoxyl group-N'-methyl nitrosourea intermediate；
Described second solvent is any one or more in petroleum ether, normal heptane, normal hexane, hexamethylene and octane；
In described extraction, after the second solvent and concentration, the mass ratio of remaining dichloromethane is (0.6～0.9): 1；
Compound A；Compound B.
Preferably, in described extraction, after the second solvent and concentration, the mass ratio of remaining dichloromethane is (0.7～0.8):
1。
Preferably, described step A) in, the temperature of reaction is room temperature.
Preferably, described step A) in, the time of reaction is 8～12h.
Preferably, described step A) particularly as follows:
Compound A, compound B being mixed in dichloromethane, ice bath stirring, to dissolving, is subsequently adding triethylamine, inertia
Gas shield, 0～5 DEG C adds the special condensing agent of card, is warming up to room temperature and reacts.
Preferably, described dichloromethane is (4～8) with the mass ratio of compound A: 1.
Preferably, described compound A, compound B, triethylamine, the mol ratio of card spy's condensing agent are 1:(0.9～1.1):
(1.9～2.1): (0.9～1.1).
Preferably, described step B) in concentrate for decompression distillation.
Preferably, described second solvent is normal heptane or petroleum ether.
Preferably, described step C) after extraction, also include:
Second solvent phase is through washing, being dried.
Compared with prior art, the invention provides a kind of N-(tert-butoxycarbonyl)-L-Leu-N'-methoxyl group-
The preparation method of N'-methyl nitrosourea intermediate, including: A) by compound A, compound B under the effect of the special condensing agent of card, in two
Chloromethanes reacts；B) dichloromethane of removing 20%～40% is concentrated；C) adding the second solvent to extract, second is molten
Agent is concentrated to give N-(tert-butoxycarbonyl)-L-Leu-N'-methoxyl group-N'-methyl nitrosourea intermediate mutually；Described second molten
Agent is any one or more in petroleum ether, normal heptane, normal hexane, hexamethylene and octane；In described extraction, the second solvent with
After concentration, the mass ratio of remaining dichloromethane is (0.6～0.9): 1.The present invention utilizes two kinds of specific mutual solvents, and
Under specific ratio, can be layered in reaction system, and make the impurity in reaction system can be dissolved in not respectively with product
With in solvent, thus reach isolated and purified effect, it is not necessary to column chromatography, simple to operate, it is suitable for industry's enlarging production, and preparation
Product has higher purity and yield.
Accompanying drawing explanation
Fig. 1 is N-(tert-butoxycarbonyl)-L-Leu-N'-methoxyl group-N'-methyl acyl of the embodiment of the present invention 1 preparation
The HPLC collection of illustrative plates of amine intermediate.
Detailed description of the invention
The invention provides a kind of N-(tert-butoxycarbonyl)-L-Leu-N'-methoxyl group-N'-methyl nitrosourea intermediate
Preparation method, including:
A) by compound A, compound B under the effect of the special condensing agent of card, react in dichloromethane；
B) dichloromethane of removing 20%～40% is concentrated；
C) add the second solvent to extract, the second solvent phase be concentrated to give N-(tert-butoxycarbonyl)-L-Leu-
N'-methoxyl group-N'-methyl nitrosourea intermediate；
Described second solvent is any one or more in petroleum ether, normal heptane, normal hexane, hexamethylene and octane；
In described extraction, after the second solvent and concentration, the mass ratio of remaining dichloromethane is (0.6～0.9): 1；
Compound A；Compound B.
The present invention utilizes two kinds of specific mutual solvents, can be layered under specific ratio, the impurity in reaction system with
Product is dissolved in different solvents respectively, thus reaches isolated and purified effect, it is not necessary to column chromatography, simple to operate, and applicable industry is put
Produce greatly, and the product of preparation has higher purity and yield.
Described step A) particularly as follows:
Compound A, compound B being mixed in dichloromethane, ice bath stirring, to dissolving, is subsequently adding triethylamine, inertia
Gas shield, 0～5 DEG C is dividedly in some parts the special condensing agent of card, warms naturally to room temperature and react.
The temperature of described reaction is preferably room temperature, and the time of reaction is preferably 8～12h.
Described dichloromethane is preferably (4～8) with the mass ratio of compound A: 1, more preferably (5～7): 1；In the present invention
Some specific embodiment in, described ratio is 6:1.
Described compound A, compound B, triethylamine, the mol ratio of card spy's condensing agent are preferably 1:(0.9～1.1): (1.9
～2.1): (0.9～1.1), more preferably 1:1.05:2:1.
After reaction terminates, system carries out concentrating the dichloromethane removing 20%～40%, preferably removes 25%～35%
Dichloromethane, in some embodiments of the invention, remove 30% dichloromethane.Present invention preferably employs decompression to steam
The method evaporated removes dichloromethane.
Then in system, add the second solvent extract.
Described second solvent is any one or more in petroleum ether, normal heptane, normal hexane, hexamethylene and octane；Excellent
Elect normal heptane or petroleum ether as.
In the present invention, after described second solvent and concentration, the mass ratio of remaining dichloromethane is preferably (0.6～0.9):
1；More preferably (0.7～0.8): 1.In some embodiments of the invention, aforementioned proportion is 3:4.
The present invention is not particularly limited for the number of times of extraction, can repeatedly extract, as being extracted twice, three times.
The second solvent phase of obtaining after extraction is concentrated i.e. can get N-(tert-butoxycarbonyl)-L-Leu-N'-methoxy
Base-N'-methyl nitrosourea intermediate.
Described N-(tert-butoxycarbonyl)-L-Leu-N'-methoxyl group-N'-methyl nitrosourea intermediate structure is as follows:
The present invention there is no particular determination to described concentration, the method for concentration that can be well known to those skilled in the art, this
The bright method preferably employing concentrating under reduced pressure.
Currently preferred, also include after extraction the second solvent phase being washed, being dried, concentrate the most again.
The present invention uses the organic solvent of particular types, special ratios, can be layered in reaction system with dichloromethane,
And enable the impurity in reaction system to be dissolved in different solvents respectively with product, thus reach isolated and purified effect, it is not necessary to
Column chromatography, simple to operate, it is suitable for industry's enlarging production, and the product of preparation has higher purity and yield.
The present invention there is no particular determination to the source of above-mentioned each raw material, can be the most commercially available.
In order to further illustrate the present invention, N-(the tert-butoxycarbonyl)-L-present invention provided below in conjunction with embodiment
The preparation method of leucine-N '-methoxyl group-N '-methyl nitrosourea intermediate is described in detail.
Embodiment 1
Joining in 5L there-necked flask by compound A 500g, compound B 467.5g, add dichloromethane 3kg, ice bath stirs
Mix molten clearly, add triethylamine 546.5g, nitrogen protect, be dividedly in some parts at 0～5 DEG C card spy condensing agent 956.7g；Naturally room is risen to
Temperature reaction 10h, the system that is evaporated to reduces 1kg, adds normal heptane 1.5kg and extracts twice, merges normal heptane layer, 1.5kg water
Washing once, anhydrous magnesium sulfate is dried, and is concentrated to give pale yellow oil 563.4g, yield 95.0%, HPLC purity 99.2%.
Detecting through HPLC, the salt that by-product card spy's condensing agent generates does not detects.HPLC collection of illustrative plates is shown in that Fig. 1, data are shown in Table 1.
Table 1 embodiment of the present invention 1 product HPLC spectrum data
<peak table>
PDA Ch1 210nm
| Peak number | Chemical combination name | Retention time | Highly | Area | Theoretical cam curve (USP) | Separating degree (USP) | Tailing factor | Area % |
| 1 | 6.495 | 2119 | 7971 | 50065 | -- | 1.353 | 0.055 | |
| 2 | 12.190 | 623 | 4020 | 67209 | 37.440 | 1.592 | 0.028 | |
| 3 | 13.483 | 8695 | 59105 | 79003 | 6.808 | 1.351 | 0.407 | |
| 4 | 14.031 | 574 | 4034 | 81269 | 2.815 | 1.550 | 0.028 | |
| 5 | 14.904 | 4044 | 32913 | 72716 | 4.181 | 0.978 | 0.226 | |
| 6 | 16.677 | 1661336 | 14386997 | 81780 | 7.803 | 1.470 | 98.982 | |
| 7 | 29.622 | 932 | 39891 | 10808 | 18.856 | 1.019 | 0.274 | |
| Amount to | 1678323 | 14534932 | 100.000 |
Embodiment 2
Joining in 5L there-necked flask by compound A 500g, compound B 203.4g, add dichloromethane 3kg, ice bath stirs
Mix molten clearly, add triethylamine 405.9g, nitrogen protect, be dividedly in some parts at 0～5 DEG C card spy condensing agent 887.0g；Naturally room is risen to
Temperature reaction 10h, the system that is evaporated to reduces 1kg, adds petroleum ether 1.0kg and extracts twice, merges petroleum ether layer, 1.0kg water
Washing once, anhydrous magnesium sulfate is dried, and is concentrated to give pale yellow oil 522.7g, yield 95%, HPLC purity 99.0%.
Detecting through HPLC, the salt that by-product card spy's condensing agent generates does not detects.
Embodiment 3
Joining in 5L there-necked flask by compound A 500g, compound B 203.4g, add dichloromethane 3kg, ice bath stirs
Mix molten clearly, add triethylamine 405.9g, nitrogen protect, be dividedly in some parts at 0～5 DEG C card spy condensing agent 887.0g；Naturally room is risen to
Temperature reaction 10h, the system that is evaporated to reduces 1kg, adds normal hexane 1.0kg and extracts twice, merges normal hexane layer, 1.0kg water
Washing once, anhydrous magnesium sulfate is dried, and is concentrated to give pale yellow oil 514.6g, yield 93%, HPLC purity 98.8%.
Detecting through HPLC, the salt that by-product card spy's condensing agent generates does not detects.
Embodiment 4
Joining in 5L there-necked flask by compound A-45 00g, compound B203.4g, add dichloromethane 3kg, ice bath stirs
Molten clearly, add triethylamine 405.9g, nitrogen protect, be dividedly in some parts at 0～5 DEG C card spy condensing agent 887.0g；Naturally it is warmed to room temperature
Reaction 10h, the system that is evaporated to reduces 1kg, adds hexamethylene 1.0kg and extracts twice, merges hexamethylene layer, and 1.0kg washes
Once, anhydrous magnesium sulfate is dried, and is concentrated to give pale yellow oil 528.3g, yield 96.0%, HPLC purity 99.0%.
Detecting through HPLC, the salt that by-product card spy's condensing agent generates does not detects.
Embodiment 5
Joining in 5L there-necked flask by compound A-45 00g, compound B203.4g, add dichloromethane 3kg, ice bath stirs
Molten clearly, add triethylamine 405.9g, nitrogen protect, be dividedly in some parts at 0～5 DEG C card spy condensing agent 887.0g；Naturally it is warmed to room temperature
Reaction 10h, the system that is evaporated to reduces 1kg, adds normal octane 1.0kg and extracts twice, merges normal octane layer, and 1.0kg washes
Once, anhydrous magnesium sulfate is dried, and is concentrated to give pale yellow oil 530.2g, yield 96.3%, HPLC purity 99.2%.
Detecting through HPLC, the salt that by-product card spy's condensing agent generates does not detects.
From above-described embodiment, the present invention prepares N-(tert-butoxycarbonyl)-L-Leu-N'-methoxyl group-N'-first
During base amide intermediate, it is not necessary to pillar layer separation, post processing is simple, and product purity, yield are the highest.
The explanation of above example is only intended to help to understand method and the core concept thereof of the present invention.It is right to it should be pointed out that,
For those skilled in the art, under the premise without departing from the principles of the invention, it is also possible to the present invention is carried out
Some improvement and modification, these improve and modify in the protection domain also falling into the claims in the present invention.
Claims (10)
1. a preparation method for N-(tert-butoxycarbonyl)-L-Leu-N'-methoxyl group-N'-methyl nitrosourea intermediate, bag
Include:
A) by compound A, compound B under the effect of the special condensing agent of card, react in dichloromethane；
B) dichloromethane of removing 20%～40% is concentrated；
C) adding the second solvent to extract, the second solvent phase is concentrated to give N-(tert-butoxycarbonyl)-L-Leu-N'-first
Epoxide-N'-methyl nitrosourea intermediate；
Described second solvent is any one or more in petroleum ether, normal heptane, normal hexane, hexamethylene and octane；
In described extraction, after the second solvent and concentration, the mass ratio of remaining dichloromethane is (0.6～0.9): 1；
Compound A；Compound B.
Preparation method the most according to claim 1, it is characterised in that in described extraction, the second solvent remains after concentrating
The mass ratio of dichloromethane be (0.7～0.8): 1.
Preparation method the most according to claim 1, it is characterised in that described step A) in, the temperature of reaction is room temperature.
Preparation method the most according to claim 1, it is characterised in that described step A) in, the time of reaction is 8～12h.
Preparation method the most according to claim 1, it is characterised in that described step A) particularly as follows:
Compound A, compound B being mixed in dichloromethane, ice bath stirring, to dissolving, is subsequently adding triethylamine, noble gas
Protection, 0～5 DEG C adds the special condensing agent of card, is warming up to room temperature and reacts.
Preparation method the most according to claim 5, it is characterised in that described dichloromethane with the mass ratio of compound A is
(4～8): 1.
Preparation method the most according to claim 5, it is characterised in that described compound A, compound B, triethylamine, Ka Te
The mol ratio of condensing agent is 1:(0.9～1.1): (1.9～2.1): (0.9～1.1).
Preparation method the most according to claim 1, it is characterised in that described step B) in concentrate for decompression distillation.
Preparation method the most according to claim 1, it is characterised in that described second solvent is normal heptane or petroleum ether.
Preparation method the most according to claim 1, it is characterised in that described step C) extraction after, also include:
Second solvent phase is through washing, being dried.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116655A (en) * | 2019-12-30 | 2020-05-08 | 天津天士力圣特制药有限公司 | Preparation method of high-optical-purity tenofovir benzyl ester phosphonamide prodrug |
| CN115286536A (en) * | 2022-07-05 | 2022-11-04 | 南京安淮创新药物研究院有限公司 | Crystallization and purification method of product after amino group in amino acid is grafted with protecting group |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4687760A (en) * | 1984-12-20 | 1987-08-18 | Sanofi | Reduced peptides which inhibit gastric secretion, process for their preparation and pharmaceutical compositions in which they are present |
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2015
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US4687760A (en) * | 1984-12-20 | 1987-08-18 | Sanofi | Reduced peptides which inhibit gastric secretion, process for their preparation and pharmaceutical compositions in which they are present |
Non-Patent Citations (2)
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| ALBAN R. PEREIRA，ET AL.: "The Carmaphycins: New Proteasome Inhibitors Exhibiting an α,β-Epoxyketone Warhead from a Marine Cyanobacterium", 《CHEMBIOCHEM》 * |
| JEAN-ALAIN FEHRENTZ，ET AL.: "Synthesis of aldehydic peptides inhibiting renin", 《INT.J.PEPTIDE PROTEIN RES.》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116655A (en) * | 2019-12-30 | 2020-05-08 | 天津天士力圣特制药有限公司 | Preparation method of high-optical-purity tenofovir benzyl ester phosphonamide prodrug |
| CN111116655B (en) * | 2019-12-30 | 2022-10-25 | 天津天士力圣特制药有限公司 | Preparation method of high-optical-purity tenofovir benzyl ester phosphonamide prodrug |
| CN115286536A (en) * | 2022-07-05 | 2022-11-04 | 南京安淮创新药物研究院有限公司 | Crystallization and purification method of product after amino group in amino acid is grafted with protecting group |
| CN115286536B (en) * | 2022-07-05 | 2023-10-27 | 南京安淮创新药物研究院有限公司 | Crystallization and purification method for product after amino group in amino acid is accessed with protecting group |
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Application publication date: 20160907 |