CN106565531A - Synthesis method for pharmaceutically acceptable salt of alkylhydrazine - Google Patents
Synthesis method for pharmaceutically acceptable salt of alkylhydrazine Download PDFInfo
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- CN106565531A CN106565531A CN201610927973.9A CN201610927973A CN106565531A CN 106565531 A CN106565531 A CN 106565531A CN 201610927973 A CN201610927973 A CN 201610927973A CN 106565531 A CN106565531 A CN 106565531A
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- boc
- pharmaceutically acceptable
- acceptable salt
- hydrazines
- alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C241/00—Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C241/02—Preparation of hydrazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/02—Compounds containing any of the groups, e.g. carbazates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/02—Compounds containing any of the groups, e.g. carbazates
- C07C281/04—Compounds containing any of the groups, e.g. carbazates the other nitrogen atom being further doubly-bound to a carbon atom
Abstract
The invention discloses a synthesis method for pharmaceutically acceptable salt of alkylhydrazine. According to the method, with hydrazine hydrate and BOC anhydride as starting raw materials, BOC hydrazine is synthesized firstly, then alkyl compounds are added in, BOC alkylhydrazine is obtained, finally BOC is removed, and the pharmaceutically acceptable salt of the corresponding alkylhydrazine is obtained in a conversion manner. According to the synthesis method, the raw materials for use are low in price and cost and easy to obtain. The synthesis method is short in synthesis route and high in yield, the obtained product is high in chemical purity, special production equipment is not needed for all reactions, and obtained intermediates and the final product do not need column chromatography and crystallization and purification.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, and in particular to a kind of pharmaceutically acceptable salt of alkyl hydrazine
Synthetic method.
Background technology
Alkyl hydrazine and its pharmaceutically acceptable salt are widely used as a kind of important chemical industry or medicine intermediate, and such as positive third
Base hydrazine hydrochloride：
N-pro-pyl hydrazine hydrochloride compound is wide because it is widely used in the active drug molecule of the various diseases of synthesis treatment
Concerned (WO2010118367, synlet, (13), 2355-2356；2004, Journal of Medicinal chemistry
47(15),3788-3799；2004 etc.).Such as it is used for synthesis treatment cardiovascular disease, chemotactic factor relevant disease is (such as asthma, mistake
Quick, the disease such as rheumatic arthritis), nervous system disease, HCV (hepatitis C), antibacterial and virus infection, immune system is related
The medicines such as disease, cancer.
And the synthesis of alkyl hydrazine and its pharmaceutically acceptable salt is rarely reported.Such as the synthesis of n-pro-pyl hydrazine hydrochloride, it is known that
Method is the method for the synthesis n-pro-pyl hydrazine hydrochloride of patent WO2010118367 report.The method with BOC hydrazines as raw material, and third
Ketone forms Schiff's base in 50 DEG C of condensations, and the alkylation at 80 DEG C obtains BOC n-pro-pyl hydrazines, finally in 2M aqueous hydrochloric acid solutions and four
Take off under hydrogen furan and obtain final product n-pro-pyl hydrazine hydrochloride.The method step is long, uses easy cytotoxic compound acetone processed, and reacts
The wastewater flow rate of generation is big, and industrial amplification cost is high, is difficult to be amplified production.
The content of the invention
The technical problem to be solved in the present invention is the defect for overcoming prior art, there is provided a kind of alkyl hydrazine it is pharmaceutically acceptable
The synthetic method of salt, the method cost hands over relatively low, and easily operation, yield are higher.
To solve above-mentioned technical problem, the technical solution used in the present invention is：
A kind of synthetic method of the pharmaceutically acceptable salt of alkyl hydrazine, comprises the following steps：
(1) hydrazine hydrate and BOC anhydride reactions are made, formula I is generated：BOC hydrazines；
(2) BOC hydrazines and formula II compound are reacted, obtains formula III：BOC alkyl hydrazines；
Wherein, R is selected from alkyl of the carbon number for 1-10, it is further preferred that R is selected from the alkane that carbon number is 3 or 4
Base, still more preferably, R is the alkyl that carbon number is 3, such as n-pro-pyl or isopropyl, most preferably n-pro-pyl.X is selected
From Cl, Br, I, OTs or OMs, most preferably, X is Br.Such as：When R is propyl group, formula II compound can be propyl bromide, propyl group
Iodine, propyl chloride, propyltoluene sulphonic acid ester, propyl Methanesulfonate etc..
(3) BOC alkyl hydrazines are converted into into pharmaceutically acceptable salt.
Preferably, comprise the following steps in step (1)：
a1：Hydrazine hydrate is dissolved in organic solvent a, is subsequently adding BOC anhydride, under conditions of less than 5 DEG C, stirring reaction；
Further preferred temperature conditionss are 0 DEG C.
a2：Reactant liquor drying, concentrating under reduced pressure, beating, decompression sucking filtration after a1 has been reacted obtains BOC hydrazines.
Preferably, organic solvent a is isopropanol in step a1.
Preferably, the organic solvent a and the envelope-bulk to weight ratio of hydrazine hydrate are 5～20ml:1g, hydrazine hydrate and BOC anhydride
Mol ratio be 1～1.5:1～2:1.
Preferably, the reaction in step (2) between BOC hydrazines and formula II is entered under conditions of organic solvent b and alkali are present
Capable.
Preferably, organic solvent b and the envelope-bulk to weight ratio of BOC hydrazines are 5～20ml:The mol ratio of 1g, alkali and BOC hydrazines is 1:
1。
Preferably, organic solvent b is selected from acetonitrile or/and tetrahydrofuran, alkali selected from potassium carbonate, sodium carbonate, potassium hydroxide or
One or more in sodium hydroxide.
Preferably, pharmaceutically acceptable salt described in step (3) is selected from hydrochlorate, sulfate, citrate, benzenesulfonic acid
Salt, hydrobromate, hydrofluoride, phosphate, acetate, propionate, oxalates, succinate, fumarate, maleate or
Tartrate.It is further preferred that BOC alkyl hydrazines are converted into BOC alkyl hydrazine hydrochlorides.
Preferably, pharmaceutically acceptable salt described in step (3) is the hydrochlorate shown in formula IV：
Preferably, step (3) also includes step：
c1：BOC alkyl hydrazines are dissolved in organic solvent c, the body of 4-12h, wherein organic solvent c and BOC alkyl hydrazines is stirred
Product weight ratio is 5～20ml:1g；
c2：Alkyl hydrazine hydrochloride is obtained after concentration, beating.
In the present invention, the chemical formula of hydrazine hydrate is NH2NH2H2O, BOC anhydride refers to Bis(tert-butoxycarbonyl)oxide, is abbreviated as
Boc2O, skeleton symbol is：OTs or OMs refer both to leaving group well-known to those skilled in the art.
The beneficial effect that the present invention is reached：
Cost of material that synthetic method of the present invention is used is low, with low cost, be readily obtained.And present invention synthesis
Route is short, yield is high, obtain product chemical purity is high, and all reactions are not required to special producing equipment, gained intermediate and most
End-product is all not required to column chromatography and crystallization purifying.Present invention reduces production cost, is easy to industry's enlarging production, provide for market
High purity product, so as to obtain higher economic benefit.
Description of the drawings
Fig. 1 is the synthetic route chart of embodiment 1 and embodiment 7；
Fig. 2 is the nucleus magnetic hydrogen spectrum figure of n-pro-pyl hydrazine hydrochloride；
Specific embodiment
Below in conjunction with the accompanying drawings the invention will be further described.Following examples are only used for clearly illustrating the present invention
Technical scheme, and can not be limited the scope of the invention with this.
The synthesis of the n-pro-pyl hydrazine hydrochloride of embodiment 1, synthetic route is shown in Fig. 1, comprises the following steps：
(1) synthesis of BOC hydrazines：Raw material hydrazine hydrate is dissolved in isopropanol (IPA) solvent, isopropanol and described hydrazine hydrate
Envelope-bulk to weight ratio (ml/g) be 5～20:1, the mol ratio that BOC anhydride, hydrazine hydrate and BOC anhydride are then added in solution is 1
～1.5:1～2:1, in 0 DEG C of degree stirring to reacting completely (about 0.5h or so), solvent clarification is evaporated to, dichloromethane is dilute
Release, anhydrous sodium sulfate drying, be concentrated under reduced pressure to give white solid.The petroleum ether beating of described white solid, petroleum ether and institute
The envelope-bulk to weight ratio of the white solid stated is：5～10:1, then obtain BOC hydrazines, yield through decompression sucking filtration：50%；
(2) synthesis of BOC n-pro-pyls hydrazine：BOC hydrazines and potassium carbonate that the BOC hydrazines that step (1) is obtained obtain step (1)
In adding acetonitrile, the envelope-bulk to weight ratio (ml/g) of acetonitrile BOC n-pro-pyl hydrazines is 5～20:1, the mol ratio of potassium carbonate and BOC hydrazines is
1～2:1, bromo propane is slowly added drop-wise in reactant liquor, and the mol ratio of bromo propane and BOC hydrazines is 1～2:1, stir after dripping
Mix complete to reaction, by filtering, washing, be dried, after concentration BOC n-pro-pyl hydrazines, yield 80-100% are obtained.
(3) synthesis of n-pro-pyl hydrazine hydrochloride：BOC n-pro-pyl hydrazines described in step (2) are dissolved in into 2M hydrochloric acid dichloromethane
(DCM) in solvent, described 2M hydrochloric acid dichloromethane and the envelope-bulk to weight ratio (ml/g) of described BOC n-pro-pyl hydrazines is 5～20:
1, stir 4～12 hours, obtain n-pro-pyl hydrazine hydrochloride, purity 97% after the beating of concentrating under reduced pressure, petroleum ether or ethyl acetate
More than, yield 75-85%.
Embodiment 2：The synthesis of BOC hydrazines：
150 milliliters of 30 grams of hydrazine hydrate and isopropanol are added in three mouthfuls of reaction bulbs with agitator, under ice-water bath cooling
60 milliliters of the aqueous isopropanol of 55.8 grams of BOC anhydride, 0-10 DEG C of degree stirring 0.5h is added to be concentrated into solution clear to reacting complete
Clearly, 100 milliliters of additions of dichloromethane, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains white solid.Gained crude product petroleum ether
200 milliliters of beating, decompression sucking filtration obtains 35.7 grams of white solid, LC purity more than 92%, yield 50%.
Embodiment 3：The synthesis of BOC hydrazines
150 milliliters of 30 grams of hydrazine hydrate and isopropanol are added in three mouthfuls of reaction bulbs with agitator, under ice-water bath cooling
120 milliliters of the aqueous isopropanol of 111.6 grams of BOC anhydride, 0-10 DEG C of degree stirring 0.5h is added to be concentrated into solution clear to reacting complete
Clearly, 100 milliliters of additions of dichloromethane, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains white solid.Gained crude product petroleum ether
200 milliliters of beating, decompression sucking filtration obtains 35.7 grams of white solid, LC purity more than 55%, yield 80%.
Embodiment 4：The synthesis of BOC n-pro-pyl hydrazines：
13.2 grams of BOC hydrazines, 13.8 grams of potassium carbonate and the milli of acetonitrile alcohol 130 are added in three mouthfuls of reaction bulbs with agitator
Rise, ice-water bath cooling is lower to add 12.3 grams of bromo propane, 4h be stirred at room temperature and extremely react complete, reduce pressure sucking filtration, solid acetonitrile 40
Milliliter rinsing.Merging filtrate and washing liquid, concentrating under reduced pressure obtains 17.4 grams of water white oil, LC purity more than 90%, yield 100%.
Embodiment 5：The synthesis of BOC n-pro-pyl hydrazines：
13.2 grams of BOC hydrazines, 13.8 grams of potassium carbonate and the milli of tetrahydrofuran 130 are added in three mouthfuls of reaction bulbs with agitator
Rise, ice-water bath cooling is lower to add 12.3 grams of bromo propane, 4h be stirred at room temperature and extremely react complete, reduce pressure sucking filtration, solid tetrahydrochysene furan
Mutter 40 milliliters and rinse.Merging filtrate and washing liquid, concentrating under reduced pressure obtains 15.7 grams of water white oil, LC purity 63%, yield 90%.
Embodiment 6：The synthesis of n-pro-pyl hydrazine hydrochloride：
17.4 grams of BOC n-pro-pyls hydrazine and 2M hydrochloric acid dichloromethane solution 90 are added in three mouthfuls of reaction bulbs with agitator
Milliliter, is stirred at room temperature 4h and extremely reacts complete, reduce pressure sucking filtration, and gained crude product 40 milliliters of beating of dichloromethane, the sucking filtration that reduces pressure is obtained
9.4 grams of white solid, LC purity more than 98%, yield 85%.
Embodiment 7：The synthesis of n-pro-pyl hydrazine hydrochloride：
17.4 grams of BOC n-pro-pyls hydrazine and 2M hydrochloric acid dichloromethane solutions are added in three mouthfuls of reaction bulbs with agitator
348 milliliters, 4h is stirred at room temperature and extremely reacts complete, reduce pressure sucking filtration, and gained crude product 40 milliliters of beating of dichloromethane, decompression is taken out
Filter to obtain 8.29 grams of white solid, LC purity more than 98%, yield 75%.
The synthesis of the isopropyl hydrazine hydrochloride of embodiment 8
17.4 grams of BOC isopropyls hydrazine and 2M hydrochloric acid dichloromethane solution 90 are added in three mouthfuls of reaction bulbs with agitator
Milliliter, is stirred at room temperature 4h and extremely reacts complete, reduce pressure sucking filtration, and gained crude product 40 milliliters of beating of dichloromethane, the sucking filtration that reduces pressure is obtained
8.9 grams of solid, LC purity more than 98%, yield 70%.
The synthesis of the n-pro-pyl hydrazine hydrochloride of embodiment 9：
What formula II compound was selected in the present embodiment synthesis step is n-pro-pyl tosylate, remaining each step and relative
Consumption is final to obtain n-pro-pyl hydrazine hydrochloride yield 78%, LC purity more than 98% with embodiment 1.
The synthesis of the normal-butyl hydrazine hydrochloride of embodiment 10：
What formula II compound was selected in the present embodiment synthesis step is n-butyl bromide, and remaining each step and relative usage are with real
Example 1 is applied, it is final to obtain normal-butyl hydrazine hydrochloride yield 75%, LC purity more than 98%.
The Tertiary butyl hydrazine hydrochloride of embodiment 11
What formula II compound was selected in the present embodiment synthesis step is tert-butyl bromide, and remaining each step and relative usage are with real
Example 1 is applied, it is final to obtain Tertiary butyl hydrazine hydrochloride yield 70%, LC purity more than 98%.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, on the premise of without departing from the technology of the present invention principle, some improvement and deformation can also be made, these improve and deform
Also should be regarded as protection scope of the present invention.
Claims (10)
1. a kind of synthetic method of the pharmaceutically acceptable salt of alkyl hydrazine, it is characterised in that comprise the following steps：
(1) hydrazine hydrate and BOC anhydride reactions are made, formula I is generated：BOC hydrazines；
(2) BOC hydrazines and formula II compound are reacted, obtains formula III：BOC alkyl hydrazines；
R-X
Ⅱ
Wherein, selected from the alkyl that carbon number is 1-10, X is selected from Cl, Br, I, OTs or OMs to R；
(3) BOC alkyl hydrazines are converted into into pharmaceutically acceptable salt.
2. the synthetic method of the pharmaceutically acceptable salt of alkyl hydrazine according to claim 1, it is characterised in that in step (1)
Comprise the following steps：
a1：Hydrazine hydrate is dissolved in organic solvent a, is subsequently adding BOC anhydride, under conditions of less than 5 DEG C, stirring reaction；
a2：Reactant liquor drying, concentrating under reduced pressure, beating, decompression sucking filtration after a1 has been reacted obtains BOC hydrazines.
3. the synthetic method of the pharmaceutically acceptable salt of alkyl hydrazine according to claim 2, it is characterised in that in step a1
Organic solvent a is isopropanol.
4. the synthetic method of the pharmaceutically acceptable salt of the alkyl hydrazine according to Claims 2 or 3, it is characterised in that it is described to have
Machine solvent a is 5～20ml with the envelope-bulk to weight ratio of hydrazine hydrate:The mol ratio of 1g, hydrazine hydrate and BOC anhydride is 1～1.5:1～2:
1。
5. the synthetic method of the pharmaceutically acceptable salt of alkyl hydrazine according to claim 1, it is characterised in that in step (2)
Reaction between BOC hydrazines and formula II is carried out under conditions of organic solvent b and alkali are present.
6. the synthetic method of the pharmaceutically acceptable salt of alkyl hydrazine according to claim 5, it is characterised in that organic solvent b
It is 5～20ml with the envelope-bulk to weight ratio of BOC hydrazines:The mol ratio of 1g, alkali and BOC hydrazines is 1:1.
7. the synthetic method of the pharmaceutically acceptable salt of the alkyl hydrazine according to claim 5 or 6, it is characterised in that You Jirong
Agent b is selected from acetonitrile or/and tetrahydrofuran, the one kind or many of alkali in potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide
Kind.
8. the synthetic method of the pharmaceutically acceptable salt of alkyl hydrazine according to claim 1, it is characterised in that in step (3)
The pharmaceutically acceptable salt is selected from hydrochlorate, sulfate, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphoric acid
Salt, acetate, propionate, oxalates, succinate, fumarate, maleate or tartrate.
9. the synthetic method of the pharmaceutically acceptable salt of alkyl hydrazine according to claim 1, it is characterised in that in step (3)
The pharmaceutically acceptable salt is the hydrochlorate shown in formula IV：
10. the synthetic method of the pharmaceutically acceptable salt of alkyl hydrazine according to claim 9, it is characterised in that step (3) is also
Including step：
c1：BOC alkyl hydrazines are dissolved in organic solvent c, the volume weight of 4-12h, wherein organic solvent c and BOC alkyl hydrazines is stirred
Amount is than being 5～20ml:1g；
c2：Alkyl hydrazine hydrochloride is obtained after concentration, beating.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109053485A (en) * | 2018-09-26 | 2018-12-21 | 吉林化工学院 | A kind of purifying process of Tertiary butyl hydrazine hydrochloride |
| CN111132959A (en) * | 2017-09-25 | 2020-05-08 | 富士胶片株式会社 | Method for producing compound and compound |
| CN113402425A (en) * | 2021-06-17 | 2021-09-17 | 常州吉恩药业有限公司 | Preparation method of high-purity tert-butyl carbazole |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111132959A (en) * | 2017-09-25 | 2020-05-08 | 富士胶片株式会社 | Method for producing compound and compound |
| CN111132959B (en) * | 2017-09-25 | 2023-07-28 | 富士胶片株式会社 | Method for producing compound and compound |
| CN109053485A (en) * | 2018-09-26 | 2018-12-21 | 吉林化工学院 | A kind of purifying process of Tertiary butyl hydrazine hydrochloride |
| CN109053485B (en) * | 2018-09-26 | 2021-01-15 | 吉林化工学院 | Purification process of tert-butyl hydrazine hydrochloride |
| CN113402425A (en) * | 2021-06-17 | 2021-09-17 | 常州吉恩药业有限公司 | Preparation method of high-purity tert-butyl carbazole |
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Application publication date: 20170419 |