CN110483392A - Synthesize the method and synthetic intermediate of the quinoline -7- base oxygroup methylcyclopropyl groups amine derivative of N-protected - Google Patents
Synthesize the method and synthetic intermediate of the quinoline -7- base oxygroup methylcyclopropyl groups amine derivative of N-protected Download PDFInfo
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- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
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- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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
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Abstract
The present invention relates to the methods and synthetic intermediate of the quinoline -7- base oxygroup methylcyclopropyl groups amine derivative of synthesis N-protected, more particularly to the preparation method and its synthetic intermediate of synthesis N-protected base-(1- (((the chloro- 6- methoxy quinoline -7- base of 4-) oxygroup) methyl) cyclopropyl) amine derivative.
Description
Technical field
The present invention relates to the method for the quinoline -7- base oxygroup methylcyclopropyl groups amine derivative of synthesis N-protected and synthesis are intermediate
Body, more particularly to synthesis N-protected base-(1- (((the chloro- 6- methoxy quinoline -7- base of 4-) oxygroup) methyl) cyclopropyl) amine are derivative
The preparation method and its synthetic intermediate of object.
Background technique
1 compound of formula, 6- (7- ((1- amino cyclopropyl) methoxyl group) -6- methoxy quinoline -4- base oxygroup)-N- methyl -
1- naphthalenecarboxamide (AL3810) or its officinal salt (such as hydrochloride) have been developed as antitumor agent, the compound also by
Referred to as E3810 and De Li is for Buddhist nun (lucitanib) (referring to Journal of Cellular and Molecular
Medicine, volume 16, the 10th phase, in December, 2012, the 2321-2330 pages and Cancer Res, on 2 15th, 2011, the
Volume 71, the 4th phase, 1396-1405).
WO2008112408 discloses 6- (7- ((1- amino cyclopropyl) methoxyl group) -6- as angiogenesis inhibitor
Methoxy quinoline-4- base oxygroup)-N- methyl-1-naphthalenecarboxamide and its small preparation method.
WO2010105761, which is disclosed, a kind of prepares 6- (7- ((1- amino cyclopropyl) methoxyl group) -6- methoxy quinoline -4-
Base oxygroup)-N- methyl-1-naphthalenecarboxamide new method, wherein N-protected base-(1- (((the chloro- 6- methoxy quinoline-of 4- of formula 2
7- yl) oxygroup) methyl) cyclopropyl) amine be this method in key intermediate:
Wherein, P is common amino protecting group, such as allyloxycarbonyl (Alloc), tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group
(Cbz), to methbxybenzyl-oxycarbonyl (PMZ) or to nitrobenzyloxycarbonyl (PNZ) etc..6- (7- ((1- ammonia is prepared by 2 compound of formula
Cyclopropyl) methoxyl group)-6- methoxy quinoline-4- base oxygroup)-N- methyl-1-naphthalenecarboxamide, reaction condition is mild, post-processing
Easy and yield is higher, is 60% or so.
About 2 compound of formula, two kinds of N-protected bases-(1- amino cyclopropyl) with formula 3 are disclosed in WO2010105761
Methanol is the preparation method of starting material:
Wherein, P is common amino protecting group, such as Alloc, BOC, Cbz, PMZ or PNZ, comprising:
Method a:
Method b:
Wherein, in method a, by 3 preparation of compounds of formula of formula, 2 compound, totally 5 steps are reacted, and route is longer, and total recovery is only
It is 23% or so.
In method b, although step reaction is that light prolongs instead by 3 preparation of compounds of formula of formula, 2 compound only single step reaction
Answer, cumbersome and conversion ratio is lower, and the reaction conversion ratio after reaction 5 hours is also only 80% or so, and product purity compared with
It is low.
There is still a need for new synthesis N-protected base-(1- (((the chloro- 6- methoxy quinoline -7- base of 4-) oxygroup) methyl) cyclopropyl)
The method of amine is to overcome the drawbacks described above of the prior art.
Summary of the invention
The invention discloses using N-protected base-(the 1- amino cyclopropyl) methanol of formula 3 as the N- of starting material preparation formula 2 guarantor
Protect the new method of base-(1- (((the chloro- 6- methoxy quinoline -7- base of 4-) oxygroup) methyl) cyclopropyl) amine:
Wherein, P is common amino protecting group, such as Alloc, BOC, Cbz, PMZ or PNZ.With the method for the prior art
It compares, especially compared with the method disclosed in WO2010105761, method of the invention is short with route, method is easy,
Yield and the high feature of product purity.For example, the purity of 2 compound of formula prepared by the method for the invention can generally achieve
95% or more, preferably 98% or more, more preferable 99% or more.
In particular, the present invention provides the methods of 2 compound of preparation formula:
This method comprises the following steps:
1) by the compound of formula 3:
It is reacted with the sulfonic acid chloride of formula RCl, with the compound of production 3A:
Wherein P is common amino protecting group, such as Alloc, BOC, Cbz, PMZ or PNZ, and R is mesyl, benzene sulfonyl
Base, p-toluenesulfonyl, to MethOxybenzenesulfonyl etc., then
2) the formula 3A compound of generation is reacted with the compound of formula 9
With the compound of production 2；Or；
2 ') formula 3A compound is reacted to the compound of production 3B with halogeno salt MX:
Wherein MX is halogeno salt, preferably sodium iodide, potassium iodide or lithium bromide；
X is halogen, preferably iodine or bromine；And
3 ') the formula 3B compound of generation is reacted with the compound of formula 9
With the compound of production 2.
In one embodiment, the present invention provides the methods of 2 compound of preparation formula:
This method comprises the following steps:
1) by the compound of formula 3:
It is reacted with the sulfonic acid chloride of formula RCl, with the compound of production 3A:
Wherein P is common amino protecting group, such as Alloc, BOC, Cbz, PMZ or PNZ, and R is mesyl, benzene sulfonyl
Base, p-toluenesulfonyl, to MethOxybenzenesulfonyl etc., and
2) the formula 3A compound of generation is reacted with the compound of formula 9
With the compound of production 2.
This method can be used following reaction process to indicate:
Process 1:
Wherein, P is common amino protecting group, such as Alloc, BOC, Cbz, PMZ, PNZ etc.；R is mesyl, benzene sulfonyl
Base, p-toluenesulfonyl, to MethOxybenzenesulfonyl etc.；
MI is sodium iodide or potassium iodide.
The step 1) of this method carries out in organic solvent in the presence of base.The alkali includes inorganic base and organic
Alkali, wherein inorganic base can be sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide etc., and organic base can be triethylamine, two different
Ethylamine, pyridine etc..Solvent for use is polar non-solute such as acetone, ethyl acetate, methylene chloride, chloroform, four
Hydrogen furans etc..Reaction carries out at 0~35 DEG C.
The step 2) of this method carries out in organic solvent in the presence of sodium iodide or potassium iodide.Solvent for use is polarity
Aprotic solvent such as acetone, ethyl acetate, methylene chloride, chloroform, tetrahydrofuran.Reaction carries out at 25~100 DEG C, such as
It is carried out under the reflux temperature of solvent.
In the above-mentioned methods, the obtained product formula 3A compound of step 1) can carry out separation and pure by conventional method
Change.Alternatively, formula 3A compound generated can also be without isolation directly with the chloro- 6- methoxy quinoline -7- alcohol of the 4- of formula 9 in iodine
One kettle way is condensed to yield 2 compound of formula under the action of changing sodium or potassium iodide.This method has a clear superiority, and reaction condition is mild,
High conversion rate, total recovery 60%~70%, the purity of 2 crude compound of gained formula is up to 95% or more, preferably 98% or more.
In another embodiment, the present invention provides the methods of 2 compound of preparation formula:
This method comprises the following steps:
1) by the compound of formula 3:
It is reacted with the sulfonic acid chloride of formula RCl, with the compound of production 3A:
Wherein P is common amino protecting group, such as Alloc, BOC, Cbz, PMZ or PNZ, and R is mesyl, benzene sulfonyl
Base, p-toluenesulfonyl, to MethOxybenzenesulfonyl etc.；Then
2 ') formula 3A compound is reacted to the compound of production 3B with halogeno salt MX:
Wherein MX is halogeno salt, preferably sodium iodide, potassium iodide or lithium bromide；
X is halogen, preferably iodine or bromine；And
3 ') the formula 3B compound of generation is reacted with the compound of formula 9
With the compound of production 2.
This method can be used following reaction process to indicate:
Process 2:
The step 1) of this method carries out in organic solvent in the presence of base.The alkali includes inorganic base and organic
Alkali, inorganic base can be sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide etc., and organic base can be triethylamine, diisopropyl
Ethylamine, pyridine etc..Solvent for use is polar non-solute such as acetone, ethyl acetate, methylene chloride, chloroform, tetrahydro furan
It mutters.Reaction carries out at 0~35 DEG C.
The step 2 of this method ') it carries out in organic solvent.Solvent for use is polar non-solute such as acetone, acetic acid
Ethyl ester, methylene chloride, chloroform, tetrahydrofuran etc..Reaction carried out at 25~100 DEG C, such as under the reflux temperature of solvent into
Row.
The step 3 of this method ') it carries out in organic solvent in the presence of base.The alkali includes inorganic base and organic
Alkali, inorganic base can be sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide etc., and organic base can be triethylamine, diisopropyl
Ethylamine, pyridine etc..Solvent for use is polar non-solute such as acetone, ethyl acetate, methylene chloride, chloroform, tetrahydro furan
It mutters.Reaction carries out at 25~100 DEG C, such as carries out under the reflux temperature of solvent.
In the above-mentioned methods, the obtained product formula 3A compound of step 1) and step 2 ') obtained product formula 3B
Compound can be separated and be purified by conventional method.
The method of above-mentioned process 2 equally has a clear superiority, and reaction condition is mild, high conversion rate, and total recovery 60%~
70%, the purity of 2 crude compound of gained formula is up to 95% or more, preferably 98% or more.
In the method for the invention, raw materials used 3 compound of formula and the compound of formula 9 are commercially available or according to this field
Known method obtains, such as can obtain according to the method disclosed in WO2010105761.
The invention further relates to the new midbody compounds for synthetic method of the present invention.
Therefore, in one embodiment, the present invention provides the midbody compound of formula 3A or its salt:
Wherein P is common amino protecting group, such as Alloc, BOC, Cbz, PMZ or PNZ, and R is mesyl, benzene sulfonyl
Base, p-toluenesulfonyl, to MethOxybenzenesulfonyl etc..
In one embodiment, the present invention provides following compounds:
Methanesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester；
4- toluenesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester；
Benzene sulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester；
4- methoxy benzenesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester；
Methanesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester；
4- toluenesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester；
Benzene sulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester；With
4- methoxy benzenesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester.
In another embodiment, the present invention provides the midbody compound of formula 3B or its salt:
Wherein P is common amino protecting group, such as Alloc, BOC, Cbz, PMZ or PNZ, X are halogen, preferably iodine or
Bromine；
Condition is that the formula 3B compound does not include N- (1- (bromomethyl) cyclopropyl)-benzyloxy-formyl amine.
In one embodiment, the present invention provides following compounds:
N- (1- (iodomethyl) cyclopropyl)-allyloxy formamide；
N- (1- (bromomethyl) cyclopropyl)-allyloxy formamide；With
N- (1- (iodomethyl) cyclopropyl)-benzyloxy-formyl amine.
The present invention is further detailed by following non-limiting embodiment.
Embodiment
Embodiment 1: the preparation of methanesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester
By in the reaction flask of 1- (methylol) cyclopropylamino allyl formate (30g, 175.4mmol) investment 500ml, add
Enter methylene chloride (300ml), be added diisopropyl ethyl amine (27.2g, 210.5mmol), 0~5 DEG C or so is cooled under stirring,
It is added dropwise mesyl chloride (25.4g, 210.5mmol), after addition, is warming up to 10 DEG C or so and reacts 5 hours.
After reaction, hydrochloric acid (1M) (200ml*2), saturated sodium bicarbonate solution (200ml), water (200ml* are successively used
2) it is filtered after anhydrous magnesium sulfate is dry with salt water (200ml*2) washing reaction liquid, separation organic phase, filtrate subtracts at 30 DEG C
Solvent is evaporated off in pressure, obtains white solid product 40.3g, yield: 92.3%.MS[M+H]+:250。
Embodiment 2: (1- (((the chloro- 6- methoxy of 4- is prepared by methanesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester
Base quinoline -7- base) oxygroup) methyl) cyclopropyl) allyl carbamate method
By the chloro- 6- methoxy quinoline -7- alcohol (18g, 86.1mmol) of 4-, KI (21.5g, 129.2mmol), K2CO3(48g,
344.4mmol) and in acetone (200ml) investment reaction flask and magnetic agitation at room temperature.Methanesulfonic acid -1- (allyl oxygen carbonyl is added
Base amino) cyclopropylmethyl ester (27.9g, 111.9mmol, 1.3eq), it is warming up to (56 DEG C) of reflux and reacts 15 hours.
Reaction solution is down to environment temperature, is filtered, with a small amount of acetone filter wash cake.30 are stirred in the water of filter cake investment 200ml
Minute.Filtering, is washed with water filter cake.Evaporated under reduced pressure filter cake obtains light gray solid 19.8g, yield 63.5%.Product purity:
98.9%.MS[M+H]+:363。
The preparation of embodiment 3:4- toluenesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester
Under nitrogen protection, compound 1- (methylol) cyclopropylamino allyl formate (2.5g, 14.6mmol) is put into
In the reaction flask of 100ml, methylene chloride (30ml), 4-dimethylaminopyridine (2.2g, 17.6mmol) is added, is cooled under stirring
0~5 DEG C or so, 4- toluene sulfonyl chloride (3.3g, 17.3mmol) is added portionwise.After addition, it is warming up to 10 DEG C or so instead
It answers 5 hours.
After reaction, successively with hydrochloric acid (1M) (30ml*2), saturated sodium bicarbonate solution (30ml), water (30ml*2) and
Salt water (30ml*2) washing reaction liquid separates organic phase, and after anhydrous magnesium sulfate is dry, filtering, filtrate depressurizes steaming at 30 DEG C
Except solvent, white solid product 4.10g is obtained, yield: 86.3%.MS[M+H]+:326。
Embodiment 4: prepare that ((((4- is chloro- by 1- by 4- toluenesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester
6- methoxy quinoline -7- base) oxygroup) methyl) cyclopropyl) allyl carbamate method
The method of reference implementation example 2 substitutes first with 4- toluenesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester
Sulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester, yield 60.4%, product purity: 94.83%.MS[M+H]+:363。
Embodiment 5: the preparation of benzene sulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester
By the reaction of compound 1- (methylol) cyclopropylamino allyl formate (2.5g, 14.6mmol) investment 100ml
In bottle, tetrahydrofuran (30ml) and sodium hydroxide (0.7g, 17.6mmol) is added, 0~5 DEG C or so is cooled under stirring, is added dropwise
Benzene sulfonyl chloride (3.0g, 17.3mmol, 1.2eq) after being added dropwise, is warming up to 10 DEG C or so and reacts 5 hours.
After reaction, it filters, filtrate decompression concentration, gained residue is dissolved with methylene chloride (30ml), methylene chloride
Mutually successively wash with water (30ml*2), salt water (30ml*2), separate organic phase, through anhydrous magnesium sulfate dry after, filter, filtrate in
Evaporating solvent under reduced pressure at 30 DEG C, residue are washed and starched with isopropyl ether, obtain white solid product 4.03g, yield 88.7%.MS[M+
H]+:312。
Embodiment 6: (1- (((the chloro- 6- methoxy of 4- is prepared by benzene sulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester
Base quinoline -7- base) oxygroup) methyl) cyclopropyl) allyl carbamate method
The method of reference implementation example 2 substitutes methanesulfonic acid-with benzene sulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester
1- (allyloxycarbonyl amino) cyclopropylmethyl ester, yield 52.2%, product purity: 97.32%.MS[M+H]+:363。
The preparation of embodiment 7:4- methoxy benzenesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester
The method of reference implementation example 3 substitutes 4- toluene sulfonyl chloride, yield 90.4% with 4- Methoxybenzenesulfonyl chloride.MS
[M+H]+:342。
Embodiment 8: (1- (((4- is prepared by 4- methoxy benzenesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester
Chloro- 6- methoxy quinoline -7- base) oxygroup) methyl) cyclopropyl) allyl carbamate method
The method of reference implementation example 2 is substituted with 4- methoxy benzenesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester
Methanesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester, yield 58.9%, product purity: 97.59%.MS[M+H]+:
363。
Embodiment 9: the preparation of methanesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester
The method of reference implementation example 1 substitutes 1- (methylol) cyclopropyl with 1- (methylol) cyclopropylamino benzyl formate
Allyl carbamate, yield 94.8%.MS[M+H]+:300。
Embodiment 10: (1- (((the chloro- 6- methoxyl group of 4- is prepared by methanesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester
Quinoline -7- base) oxygroup) methyl) cyclopropyl) benzyq carbamate method
The method of reference implementation example 2 substitutes methanesulfonic acid -1- with methanesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester
(allyloxycarbonyl amino) cyclopropylmethyl ester, yield 78.0%, product purity: 99.0%.MS[M+H]+:413。
The preparation of embodiment 11:4- toluenesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester
The method of reference implementation example 3 substitutes 1- (methylol) cyclopropyl with 1- (methylol) cyclopropylamino benzyl formate
Allyl carbamate, yield 90.8%.MS[M+H]+:376。
Embodiment 12: (1- (((the chloro- 6- of 4- is prepared by 4- toluenesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester
Methoxy quinoline -7- base) oxygroup) methyl) cyclopropyl) benzyq carbamate method
The method of reference implementation example 2 substitutes methylsulphur with 4- toluenesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester
Acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester, yield 64.5%, product purity: 99.67%.MS[M+H]+:413。
Embodiment 13: the preparation of benzene sulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester
The method of reference implementation example 3 substitutes 1- (methylol) cyclopropyl with 1- (methylol) cyclopropylamino benzyl formate
Allyl carbamate, yield 87.4%.MS[M+H]+:362。
Embodiment 14: (1- (((the chloro- 6- methoxyl group of 4- is prepared by benzene sulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester
Quinoline -7- base) oxygroup) methyl) cyclopropyl) benzyq carbamate method
The method of reference implementation example 2 substitutes methanesulfonic acid -1- with benzene sulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester
(allyloxycarbonyl amino) cyclopropylmethyl ester, yield 68.5%, product purity: 98.95%.MS[M+H]+:413。
The preparation of embodiment 15:4- methoxy benzenesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester
The method of reference implementation example 3 substitutes 1- (methylol) cyclopropyl with 1- (methylol) cyclopropylamino benzyl formate
Allyl carbamate, yield 92.3%.MS[M+H]+:362。
Embodiment 16: prepare that ((((4- is chloro- by 1- by 4- methoxy benzenesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester
6- methoxy quinoline -7- base) oxygroup) methyl) cyclopropyl) benzyq carbamate method
The method of reference implementation example 2 substitutes first with 4- methoxy benzenesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester
Sulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester, yield 60.7%, product purity: 99.60%.MS[M+H]+:413。
The preparation of embodiment 17:N- (1- (iodomethyl) cyclopropyl)-allyloxy formamide
By methanesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester (5.0g, 20.0mmol), potassium iodide (9.3g,
56.0mmol) and in the reaction flask of acetone (65ml) investment 100ml, it is warming up to back flow reaction 5 hours.
Reaction solution is down to room temperature, is filtered, evaporated under reduced pressure filtrate, 80ml ethyl acetate is added into residue, successively uses
Water (50ml*3), salt water (50ml*3) wash organic phase, and by organic phase after anhydrous magnesium sulfate is dry, filtering, filtrate decompression is steamed
Dry, residue is washed and starched with isopropyl ether, obtains white solid 5.18g, yield 92.2%.MS[M+H]+:282。
Embodiment 18: (1- (((the chloro- 6- methoxyl group of 4- is prepared by N- (1- (iodomethyl) cyclopropyl)-allyloxy formamide
Quinoline -7- base) oxygroup) methyl) cyclopropyl) allyl carbamate method
At room temperature, by the chloro- 6- methoxy quinoline -7- alcohol (1.8g, 8.8mmol) of 4-, potassium carbonate (4.9g, 35.2mmol) and
Acetone (20ml) is put into reaction flask, magnetic agitation.Addition N- (1- (iodomethyl) cyclopropyl)-allyloxy formamide (3.1g,
11.2mmol), it is warming up to back flow reaction 15 hours.
After reaction, reaction solution is down to environment temperature, filtered, with a small amount of acetone filter wash cake.Filter cake puts into 20ml's
30min is stirred in water.Filtering, is washed with water filter cake.Evaporated under reduced pressure filter cake obtains light gray solid 2.14g, yield 68.7%, product
Purity: 98.71%.MS[M+H]+:363。
The preparation of embodiment 19:N- (1- (bromomethyl) cyclopropyl)-allyloxy formamide
The method of reference implementation example 17 substitutes potassium iodide, yield 96.8% with lithium bromide.MS[M+H]+:235。
Embodiment 20: (1- (((the chloro- 6- methoxyl group of 4- is prepared by N- (1- (bromomethyl) cyclopropyl)-allyloxy formamide
Quinoline -7- base) oxygroup) methyl) cyclopropyl) allyl carbamate method
Under nitrogen protection, by the chloro- 6- methoxy quinoline -7- alcohol (1.8g, 8.8mmol) of 4-, potassium carbonate (4.9g,
35.2mmol), in acetone (20ml) investment reaction flask, magnetic agitation.N- (1- (bromomethyl) cyclopropyl)-allyloxy first is added
Amide (2.6g, 11.2mmol) is warming up to reflux, reacts about 3 days.
After reaction, oil bath is removed, reaction solution is down to environment temperature, is filtered, with a small amount of acetone filter wash cake.Filter cake is thrown
Enter in the water of 20ml and stirs 30 minutes.Filtering, is washed with water filter cake.Evaporated under reduced pressure filter cake obtains light gray solid 2.01g, yield
64.4%, product purity: 99.24%.MS[M+H]+:363。
The preparation of embodiment 21:N- (1- (iodomethyl) cyclopropyl)-benzyloxy-formyl amine
By methanesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester (5.0g, 13.9mmol, 1.0eq), potassium iodide
(6.4g, 38.8mmol, 2.8eq) and acetone (50ml) are put into the reaction flask of 100ml, are warming up to back flow reaction 15 hours.
Reaction solution is down to room temperature, is filtered, in 35 DEG C or so evaporated under reduced pressure filtrates, 60ml acetic acid second is added into residue
Ester successively washes organic phase with water (40ml*2), salt water (40ml*3), dries then evaporated under reduced pressure organic phase with anhydrous magnesium sulfate,
Residue is washed and starched with isopropyl ether, obtains white solid product 4.29g, yield 93.8%.MS[M+H]+:332。
Embodiment 22: (1- (((the chloro- 6- methoxyl group quinoline of 4- is prepared by N- (1- (iodomethyl) cyclopropyl)-benzyloxy-formyl amine
Quinoline -7- base) oxygroup) methyl) cyclopropyl) allyl carbamate method
The method of reference implementation example 18 substitutes N- (1- (iodine first with N- (1- (iodomethyl) cyclopropyl)-benzyloxy-formyl amine
Base) cyclopropyl)-allyloxy formamide, yield 72.2%, product purity: 99.80%.MS[M+H]+:413。
The preparation of embodiment 23:N- (1- (bromomethyl) cyclopropyl)-benzyloxy-formyl amine
The method of reference implementation example 21 substitutes potassium iodide, yield 92.3% with lithium bromide.MS[M+H]+:285。
Embodiment 24: (1- (((the chloro- 6- methoxyl group quinoline of 4- is prepared by N- (1- (bromomethyl) cyclopropyl)-benzyloxy-formyl amine
Quinoline -7- base) oxygroup) methyl) cyclopropyl) allyl carbamate method
The method of reference implementation example 20 substitutes N- (1- (bromine first with N- (1- (bromomethyl) cyclopropyl)-benzyloxy-formyl amine
Base) cyclopropyl)-allyloxy formamide, yield 65.5%, product purity: 99.66%.MS[M+H]+:413。
Embodiment 25: (1- (((the chloro- 6- methoxyl group quinoline of 4- is prepared by N- (1- (bromomethyl) cyclopropyl)-benzyloxy-formyl amine
Quinoline -7- base) oxygroup) methyl) cyclopropyl) allyl carbamate method
Under nitrogen protection, by the chloro- 6- methoxy quinoline -7- alcohol (1.8g, 8.8mmol) of 4-, potassium carbonate (4.9g,
35.2mmol), in potassium iodide (2.2g, 13.2mmol) acetone (20ml) investment reaction flask, magnetic agitation.N- (1- (bromine first is added
Base) cyclopropyl)-benzyloxy-formyl amine (3.2g, 11.2mmol), it is warming up to back flow reaction about 15 hours.
After reaction, oil bath is removed, reaction solution is down to environment temperature, is filtered, with a small amount of acetone filter wash cake.Filter cake is thrown
Enter and stirs 30min in the water of 20ml.Filtering, is washed with water filter cake.Evaporated under reduced pressure filter cake obtains light pink solid product 2.43g, receives
Rate 66.9%, product purity: 99.39%.MS[M+H]+:413。
Claims (10)
1. the method for 2 compound of preparation formula:
This method comprises the following steps:
1) by the compound of formula 3:
It is reacted with the sulfonic acid chloride of formula RCl, with the compound of production 3A:
Wherein P is amino protecting group, such as Alloc, BOC, Cbz, PMZ or PNZ, and R is mesyl, benzenesulfonyl, to toluene
Sulfonyl or to MethOxybenzenesulfonyl, then
2) the formula 3A compound of generation is reacted with the compound of formula 9
With the compound of production 2；Or；
2 ') formula 3A compound is reacted to the compound of production 3B with halogeno salt MX:
Wherein MX is halogeno salt, preferably sodium iodide, potassium iodide or lithium bromide；
X is halogen, preferably iodine or bromine；And
3 ') the formula 3B compound of generation is reacted with the compound of formula 9
With the compound of production 2.
2. method described in claim 1, wherein step 1) carries out in organic solvent in the presence of base, and the alkali includes
Inorganic base and organic base, inorganic base can be sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide etc., and organic base can be three
Ethamine, diisopropyl ethyl amine, pyridine, solvent for use be polar non-solute for example acetone, ethyl acetate, methylene chloride,
Chloroform, tetrahydrofuran, reaction carry out at 0~35 DEG C.
3. method of any of claims 1 or 2, wherein step 2) in the presence of sodium iodide or potassium iodide in organic solvent into
Row, solvent for use are polar non-solute such as acetone, ethyl acetate, methylene chloride, chloroform, tetrahydrofuran, are reacted 25
It carries out at~100 DEG C, such as is carried out under the reflux temperature of solvent.
4. method described in claims 1 to 3 any one, wherein the obtained product formula 3A compound of step 1) is without isolation
Directly one kettle way is condensed to yield 2 compound of formula under the action of sodium iodide or potassium iodide with 9 compound of formula.
5. method described in claim 1, wherein step 2 ') carry out in organic solvent, solvent for use is that aprotic, polar is molten
Agent such as acetone, ethyl acetate, methylene chloride, chloroform, tetrahydrofuran, reaction carry out at 25~100 DEG C, such as in solvent
It is carried out under reflux temperature.
6. method described in claim 1 or 5, wherein step 3 ') carry out in organic solvent in the presence of base, the alkali
Comprising inorganic base and organic base, inorganic base can be sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide etc., and organic base can be with
It is triethylamine, diisopropyl ethyl amine, pyridine etc., solvent for use is polar non-solute such as acetone, ethyl acetate, dichloro
Methane, chloroform, tetrahydrofuran, reaction carries out at 25~100 DEG C, such as carries out under the reflux temperature of solvent.
7. the compound or its salt of formula 3A:
Wherein P is amino protecting group, such as Alloc, BOC, Cbz, PMZ or PNZ, and R is mesyl, benzenesulfonyl, to toluene
Sulfonyl, to MethOxybenzenesulfonyl etc..
8. compound as claimed in claim 7, is selected from:
Methanesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester；
4- toluenesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester；
Benzene sulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester；
4- methoxy benzenesulfonic acid -1- (allyloxycarbonyl amino) cyclopropylmethyl ester；
Methanesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester；
4- toluenesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester；
Benzene sulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester；With
4- methoxy benzenesulfonic acid -1- (benzyloxycarbonyl amino) cyclopropylmethyl ester.
9. the compound or its salt of formula 3B:
Wherein P is amino protecting group, such as Alloc, BOC, Cbz, PMZ or PNZ,
X is halogen, preferably iodine or bromine；
Condition be do not include N- (1- (bromomethyl) cyclopropyl)-benzyloxy-formyl amine.
10. compound as claimed in claim 9, is selected from:
N- (1- (iodomethyl) cyclopropyl)-allyloxy formamide；
N- (1- (bromomethyl) cyclopropyl)-allyloxy formamide；With
N- (1- (iodomethyl) cyclopropyl)-benzyloxy-formyl amine.
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