CN106957255A - Methylisoindoline of 5 bromines of one kind (R) N Boc 1 and its preparation method and application - Google Patents
Methylisoindoline of 5 bromines of one kind (R) N Boc 1 and its preparation method and application Download PDFInfo
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- CN106957255A CN106957255A CN201710191789.7A CN201710191789A CN106957255A CN 106957255 A CN106957255 A CN 106957255A CN 201710191789 A CN201710191789 A CN 201710191789A CN 106957255 A CN106957255 A CN 106957255A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides methylisoindoline of 5 bromines of one kind (R) N Boc 1 and its preparation method and application; (R) 4 bromine α phenyl ethylamines lewis acid effect under with polyformaldehyde reaction; obtain the methylisoindoline of (R) 5 bromine 1; and then the methylisoindoline of 5 bromines of (R) N Boc 1 is protected to secondary amino group using tertbutyloxycarbonyl; the cyclic method and step novel and unique; easily operated, yield is higher.Split the bromine α phenyl ethylamines of preparing raw material (R) 4 for obtaining chirality first using resolution reagent, and then prepare the methylisoindoline of (R) 5 bromine 1, allow to that the scale of construction is greatly reduced, the scale of construction is significantly reduced, the fractionation of whole process, which is wasted, also significantly to be reduced.The raw material of the whole preparation method of the present invention is easy to get, and technological operation is simple, low cost, with higher actual application value.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be related to one kind bromo- 1- methylisoindolines of (R)-N-Boc-5- and its
Preparation method and application.
Background technology
T-3811, English name Gatifloxacin is a carbostyril compound, its chemical entitled 1- cyclopropyl-
8- (difluoro-methoxy) -7- [(1R) -1- methyl -2,3- dihydro -1H- iso-indoles -5- bases] -4- Oxoquinoline-3-carboxylic acids, it is changed
Learn structural formula as follows：
T-3811 is a kind of New-type wide-spectrum Comprecin, and it not only maintains Comprecin to G- bacterium
Antibacterial activity, the antibacterial activity of G+ bacterium is also remarkably reinforced, clinic be mainly used in treat infection in respiratory system, urinary system togetherness
The disease such as dye and skin, soft tissue infection.Quinolone parent nucleus 6 goes the fluorine removal can not only to improve activity, Er Qieke in its structure
Reduce adverse drug reaction.
CN105837555A discloses T-3811 and its middle preparation, the T-3811 midbody compound
3 preparation flow is as follows：
The preparation flow of T-3811 is as follows：
With compound 5 it is raw material i.e. in CN105837555A, it is anti-with connection boric acid pinacol ester or triisopropyl borate ester
Should, compound 4 is obtained, the bromo- 1- cyclopropyl -8- difluoro-methoxies-Isosorbide-5-Nitrae-dihydro -4- Oxoquinoline-3-carboxylic acid second of 7- is separately added into
Ester, palladium catalyst and inorganic alkali solution reaction generation compound 3；And compound 2 and Jia Leisha are obtained by hydrolysis, reduction reaction
Star (compound 1).It can be seen that needing that ketone is converted into alkane in final step when preparing T-3811 by midbody compound 3
Base, the step yield is relatively low.
According to the side chain of T-3811 can be learnt with backstepping T-3811 side chain can by following structure the bromo- 1- of Boc-5-
Methylisoindoline conversion is obtained：
In the art, also not it has been proposed that by the high conversion preparation method of the bromo- 1- methylisoindolines of Boc-5-,
The preparation of the bromo- 1- methylisoindolines of Boc-5- is the emphasis studied at present.
The content of the invention
For prior art, it is an object of the invention to provide one kind bromo- 1- methylisoindolines of (R)-N-Boc-5- and
Its preparation method and application, this method are simple, and raw material is easy to get, it is easy to operate, and yield is higher, low cost, with higher reality
Application value.
For up to this purpose, the present invention uses following technical scheme：
On the one hand, the present invention provides the preparation method of one kind bromo- 1- methylisoindolines of (R)-N-Boc-5-, methods described
Comprise the following steps：
(1) the bromo- α-phenylethylamines of (R) -4- lewis acid effect under with polyformaldehyde reaction, obtain the bromo- 1- first of (R) -5-
Base isoindoline, reaction equation is as follows：
(2) secondary amino group in the bromo- 1- methylisoindolines of (R) -5- is obtained into (R)-N- using tertbutyloxycarbonyl protection
The bromo- 1- methylisoindolines of Boc-5-, reaction equation is as follows：
In the present invention, the bromo- 1- methylisoindolines of (R) -5- can be obtained by the annulation described in step (1),
Its high income, it is easy to operate.The bromo- 1- methylisoindolines of (R) -5- of tertbutyloxycarbonyl protection are then obtained by step (2).
Preferably, step (1) described lewis acid is dilute sulfuric acid, anhydrous zinc chloride, alchlor, trifluoroacetic acid, tetrachloro
Change in titanium or BFEE any one or at least two combination, preferred trifluoroacetic acid.
Preferably, the mol ratio of the bromo- α-phenylethylamines of (R) -4- described in step (1) and paraformaldehyde is 1:(1.5-3), for example
1:1.5、1:1.8、1:2、1:2.2、1:2.4、1:2.6、1:2.8 or 1:3.
Preferably, the temperature of step (1) described reaction be 20-60 DEG C, such as 20 DEG C, 23 DEG C, 25 DEG C, 28 DEG C, 30 DEG C, 33
DEG C, 35 DEG C, 38 DEG C, 40 DEG C, 43 DEG C, 45 DEG C, 48 DEG C, 50 DEG C, 53 DEG C, 55 DEG C, 58 DEG C or 60 DEG C.
Preferably, the solvent of step (1) described reaction be glacial acetic acid, toluene, benzene or acetonitrile in any one or at least
Two kinds of combination.
Preferably, the time of step (1) described reaction is 4-7 hours, such as 4 hours, 4.5 hours, 5 hours, it is 5.5 small
When, 6 hours, 6.5 hours or 7 hours.
Preferably, step (1) reaction is carried out under protective gas protection, the preferred nitrogen of protective gas.
Preferably, the bromo- α-phenylethylamines of (R) -4- described in step (1) are prepared by raw material of parabromoacetophenone.
Preferably, the preparation method of the bromo- α-phenylethylamines of (R) -4- comprises the following steps described in step (1)：
A, parabromoacetophenone and ammonium formate reaction obtain the bromo- phenyl ethylamines of 4-, and reaction equation is as follows：
B, using chiral resolving agent the bromo- phenyl ethylamines of 4- split obtaining the bromo- α-phenylethylamines of 4-, reaction equation is as follows：
Preferably, the mol ratio of parabromoacetophenone and ammonium formate described in step A is 1:3.5-1:6, such as 1:3.5、1:
3.8、1:4、1:4.3、1:4.5、1:4.8、1:5、1:5.2、1:5.5、1:5.8 or 1:6.
Preferably, the condition reacted described in step A is：First 110-130 DEG C (such as 110 DEG C, 115 DEG C, 120 DEG C,
125 DEG C or 130 DEG C) under react 2-4 hours (such as 2 hours, 2.5 hours, 3 hours, 3.5 hours or 4 hours), be then warming up to
170-190 DEG C (such as 170 DEG C, 175 DEG C, 180 DEG C, 185 DEG C or 190 DEG C), reaction 4-10 hours (such as 4 hours, 4.5 hours,
5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours or 10 are small
When).
Preferably, chiral resolving agent described in step B and the mol ratio of the bromo- phenyl ethylamines of 4- are (0.8-1.4):1, such as 0.8:
1、0.9:1、1:1、1.1:1、1.2:1、1.3:1 or 1.4:1, preferably 1:1.
Preferably, chiral resolving agent described in step B is in D- mandelic acids, D- tartaric acid or D- dibenzoyl tartaric acid
Any one or at least two combination.
Preferably, the temperature reacted described in step B be 40-80 DEG C, such as 40 DEG C, 45 DEG C, 48 DEG C, 50 DEG C, 55 DEG C, 58
DEG C, 60 DEG C, 65 DEG C, 68 DEG C, 70 DEG C, 75 DEG C, preferably 78 DEG C or 80 DEG C, 60 DEG C.
Preferably, the solvent reacted described in step B is isopropanol, ethanol, dimethylformamide or 1-METHYLPYRROLIDONE
In any one or at least two combination.
Preferably, the secondary amino group in step (2) the bromo- 1- methylisoindolines by (R) -5- is protected using tertbutyloxycarbonyl
The method of shield is：(R) the bromo- 1- methylisoindolines of -5- are obtained in the presence of organic base with Boc (tertbutyloxycarbonyl) anhydride reaction
To the bromo- 1- methylisoindolines of (R)-N-Boc-5-.
Preferably, the described bromo- 1- methylisoindolines of (R) -5- are 1 with the mol ratio of Boc acid anhydrides:(1-1.5), such as 1:
1、1:1.1、1:1.2、1:1.3、1:1.4 or 1:1.5.
Preferably, the organic base is DMAP or the carbon -7- alkene (DBU) of 1,8- diazabicylo 11.
Preferably, temperature of the described bromo- 1- methylisoindolines of (R) -5- in the presence of organic base with Boc anhydride reactions
For room temperature.
Preferably, time of the described bromo- 1- methylisoindolines of (R) -5- in the presence of organic base with Boc anhydride reactions
For 4-6 hours, such as 4 hours, 4.3 hours, 4.5 hours, 4.8 hours, 5 hours, 5.3 hours, 5.5 hours, 5.8 hours or 6
Hour.
Preferably, the solvent of step (2) described reaction is dichloromethane and/or chloroform.
In the present invention, in structural formula as described above, Me represents methyl.
On the other hand, the invention provides the bromo- 1- first of (R)-N-Boc-5- that preparation method as described above is prepared
Base isoindoline.
On the other hand, the invention provides the bromo- 1- first of (R)-N-Boc-5- that preparation method as described above is prepared
Application of the base isoindoline in antibacterials preparation.
Preferably, the antibacterials are T-3811.
The bromo- 1- methylisoindolines of (R)-N-Boc-5- that the present invention is prepared can be as antibacterials T-3811
Preparing raw material.
Relative to prior art, the invention has the advantages that：
(1) present invention is produced under lewis acid effect using the bromo- α-phenylethylamines of (R) -4- with polyformaldehyde reaction come closed loop
The method of the bromo- 1- methylisoindolines of raw (R) -5-, the cyclic method and step novel and unique, it is easy to operate, yield is higher so that
Whole production cost declines to a great extent, the process efficiency greatly improved.
(2) present invention splits the bromo- α-phenylethylamines of preparing raw material (R) -4- for obtaining chirality using resolution reagent first, and then
Prepare the bromo- 1- methylisoindolines of (R) -5- so that the scale of construction (volume required for reaction) can be greatly reduced, makes body
Amount significantly reduces, and the fractionation of whole process, which is wasted, also significantly to be reduced.
(3) raw material of preparation method of the invention is easy to get, and technological operation is simple, low cost, with higher practical application
Value.
Embodiment
Technical scheme is further illustrated below by embodiment.Those skilled in the art should be bright
, the embodiment be only to aid in understand the present invention, be not construed as to the present invention concrete restriction.
Embodiment 1
(1) preparation of the bromo- phenyl ethylamines of 4-
Parabromoacetophenone 1000g, ammonium formate 1445g are added in 5L reaction bulb, 120 degree, two originals are slowly heated to
Slowly dissolving is in liquid to material, opens stirring, is kept for 120 degree of 2 hours.Then reaction temperature is raised to 180 degree, and is incubated 5
Hour.Stop reaction, after cooling, add water, dichloromethane, layering, organic phase concentration, then add 670 milliliters of concentrated hydrochloric acids and 1000 millis
Rise water, backflow, 1-2 hour, reactant first had solid, rear clarification, then a large amount of precipitation solids, and reaction terminates, it is slightly cold after, add
1000 milliliters of toluene, are cooled to room temperature under stirring.Filtering, solid again with toluene is fully washed twice, and solid drying obtains product
Hydrochloride, it is neutralized with NaOH, dichloromethane extraction, dries concentration, vacuum distillation obtains 814 grams of sterling, yield
81%.1H NMR(CDCl3,400MHz)1.35(d,3H),1.47(bs,2H),4.09(q,1H),7.22(d,2H),7.44(d,
2H)。
(2) preparation of the bromo- α-phenylethylamines of (R) -4-
600 grams of R-MAs are added in 2900 milliliters of isopropanols, 1500 milliliters of alcohol mixed solutions, are heated to 60 degree, complete
Fully dissolved, is slow added into 790 grams of bromo- phenyl ethylamines of 4- (heat release).Room temperature is naturally cooled to, overnight, stirring, filtering drying is obtained
660 grams of crystal.Add it to 2000 milliliters of isopropanols, in 1100 milliliters of alcohol mixed solutions, be heated to 60 degree, crystal is complete
Dissolving, is cooled to room temperature, overnight, stirs, filtering, and a small amount of acetone washing, drying obtains 510 grams of crystal.It is used into 4M hydroxides
Sodium solution is neutralized to alkalescence, and dichloromethane is extracted three times, and drying is concentrated to give 260.7 grams of colourless liquid, yield 33%.Specific rotation
[a]=+ 24 (C1, CDCl3)；1H NMR(CDCl3,400MHz)1.35(d,3H),1.47(bs,2H),4.09(q,1H),7.22
(d,2H),7.44(d,2H)。
(3) preparation of the bromo- 3- methylisoindolines of (R) -6-
The bromo- α-phenylethylamines of 200g (R) -4- are dissolved in 3000 milliliters of glacial acetic acid, and 30ml milliliters of trifluoroacetic acids are added dropwise, and reaction is mixed
The lower reaction 12 hours of 40 degree of compound.It is concentrated under reduced pressure, residue is dissolved in 3L ethyl acetate, and saturated sodium carbonate solution is washed, washes, does
It is dry, it is concentrated under 500 milliliters, stirring and is slowly added to 1000 milliliters of petroleum ethers, be stirred overnight, filter, this step is not purified directly
Tap into row next step.
In order to be characterized to its structure, the product of the step is purified into the bromo- 3- methyl iso-indoles of (R) -6-
The product of the hydrochloride of quinoline, the nuclear-magnetism characterize data of structure is as follows：1H NMR(CDCl3,400MHz)1.57(d,3H),4.47
(dd,2H),4.82(m,1H),7.31(d,1H),7.58(d,1H),7.67(s,1H),9.86(s,1H),10.36(s,1H)。
(4) preparation of the bromo- 1- methylisoindolines of (R)-N-Boc-5-
150g (R) -6- bromo- 3- methylisoindolines (2000 milliliters) dissolvings of dichloromethane, while adding 4- diformazan ammonia
Yl pyridines 3g, stirring is lower to be added dropwise 168g Boc acid anhydrides, reacts at room temperature 3 hours.600 milliliters of saturated sodium bicarbonate solution is added,
Solid 3- alanine 15g are added, continue to stir 5 hours.Layering, organic phase dries concentration, residue with ethyl acetate and oil
Ether 15 to 1 is recrystallized, and obtains off-white powder 176g, yield 85%.1H NMR(CDCl3,400MHz)1.48(dd,3H),
1.57(s,9H),4.52-4.62(m,1H),4.62-4.76(m,1H),4.92-5.06(m,1H),7.42(dd,1H),7.35
(dd,1H),7.39(s,1H)。
Embodiment 2
(1) preparation of the bromo- phenyl ethylamines of 4-
Parabromoacetophenone 1000g, ammonium formate 950g are added in 5L reaction bulb, 120 degree, two raw materials are slowly heated to
Slowly dissolving is in liquid, opens stirring, is kept for 120 degree of 2 hours.Then reaction temperature is raised to 180 degree, and is incubated 5 small
When.Stop reaction, after cooling, add water, dichloromethane, layering, organic phase concentration, then add 670 milliliters of concentrated hydrochloric acids and 1000 milliliters
Water, backflow, 1-2 hour, reactant first had solid, rear clarification, then a large amount of precipitation solids, and reaction terminates, it is slightly cold after, add
1000 milliliters of toluene, are cooled to room temperature under stirring.Filtering, solid again with toluene is fully washed twice, and solid drying obtains product
Hydrochloride, it is neutralized with NaOH, dichloromethane extraction, dries concentration, vacuum distillation obtains 698 grams of sterling, yield
69.4%.1H NMR(CDCl3,400MHz)1.35(d,3H),1.47(bs,2H),4.09(q,1H),7.22(d,2H),7.44
(d,2H)。
(2) preparation of the bromo- α-phenylethylamines of (R) -4-
600 grams of R-MAs are added in 2900 milliliters of isopropanols, 1500 milliliters of alcohol mixed solutions, are heated to 40 degree, complete
Fully dissolved, is slow added into the bromo- phenyl ethylamines of 4-, and it is 0.8 with the mol ratio of the bromo- phenyl ethylamines of 4- to make R-MA:1 (heat release).From
Room temperature so is cooled to, overnight, stirring, filtering drying obtains 560 grams of crystal.Add it to 2000 milliliters of isopropanols, 1100 millis
Rise in alcohol mixed solution, be heated to 60 degree, crystal is completely dissolved, be cooled to room temperature, overnight, stir, filtering, a small amount of acetone is washed
Wash, drying obtains 390 grams of crystal.It is neutralized to alkalescence with 4M sodium hydroxide solutions, dichloromethane is extracted three times, dries concentration
Obtain 195.2 grams of colourless liquid, yield 24.7%.Specific rotation [a]=+ 24 (C1, CDCl3)。
(3) preparation of the bromo- 3- methylisoindolines of (R) -6-
The bromo- α-phenylethylamines of 200g (R) -4- and 90g paraformaldehydes are dissolved in 3000 milliliters of glacial acetic acid, and 30ml milliliters three are added dropwise
Fluoroacetic acid, the lower reaction 12 hours of 40 degree of reactant mixture.It is concentrated under reduced pressure, residue is dissolved in 3L ethyl acetate, and saturated sodium carbonate is molten
Liquid is washed, and is washed, and is dried, is concentrated into 500 milliliters, and 2N ether hydrogen chloride solution stirring, after 30 minutes, mistake are slowly added dropwise under stirring
Filter, this step, which is not purified, directly carries out next step.
In order to be characterized to its structure, the product of the step is purified into the bromo- 3- methyl iso-indoles of (R) -6-
The product of the hydrochloride of quinoline, the nuclear-magnetism characterize data of structure is as follows：1H NMR(CDCl3,400MHz)1.57(d,3H),4.47
(dd,2H),4.82(m,1H),7.31(d,1H),7.58(d,1H),7.67(s,1H),9.86(s,1H),10.36(s,1H)。
(4) preparation of the bromo- 1- methylisoindolines of (R)-N-Boc-5-
150g (R) -6- bromo- 3- methylisoindolines (2000 milliliters) dissolvings of dichloromethane, while adding 4- diformazan ammonia
Yl pyridines 3g, stirring is lower to be added dropwise 131g Boc acid anhydrides, reacts at room temperature 3 hours.600 milliliters of saturated sodium bicarbonate solution is added,
Solid 3- alanine 5g are added, continue to stir 5 hours.Layering, organic phase dries concentration, residue with ethyl acetate and petroleum ether
15 to 1 are recrystallized, and obtain off-white powder 153g, yield 74%.1H NMR(CDCl3,400MHz)1.48(dd,3H),
1.57(s,9H),4.52-4.62(m,1H),4.62-4.76(m,1H),4.92-5.06(m,1H),7.42(dd,1H),7.35
(dd,1H),7.39(s,1H)。
Embodiment 3
(1) preparation of the bromo- phenyl ethylamines of 4-
Parabromoacetophenone 1000g, ammonium formate 1900g are added in 5L reaction bulb, 120 degree, two originals are slowly heated to
Slowly dissolving is in liquid to material, opens stirring, is kept for 120 degree of 2 hours.Then reaction temperature is raised to 180 degree, and is incubated 5
Hour.Stop reaction, after cooling, add water, dichloromethane, layering, organic phase concentration, then add 670 milliliters of concentrated hydrochloric acids and 1000 millis
Rise water, backflow, 1-2 hour, reactant first had solid, rear clarification, then a large amount of precipitation solids, and reaction terminates, it is slightly cold after, add
1000 milliliters of toluene, are cooled to room temperature under stirring.Filtering, solid again with toluene is fully washed twice, and solid drying obtains product
Hydrochloride, it is neutralized with NaOH, dichloromethane extraction, dries concentration, vacuum distillation obtains 810 grams of sterling, yield
80.6%.1H NMR(CDCl3,400MHz)1.35(d,3H),1.47(bs,2H),4.09(q,1H),7.22(d,2H),7.44
(d,2H)。
(2) preparation of the bromo- α-phenylethylamines of (R) -4-
600 grams of R-MAs are added in 2900 milliliters of isopropanols, 1500 milliliters of alcohol mixed solutions, are heated to 80 degree, complete
Fully dissolved, is slow added into the bromo- phenyl ethylamines of 4-, and it is 1.4 with the mol ratio of the bromo- phenyl ethylamines of 4- to make R-MA:1 (heat release).From
Room temperature so is cooled to, overnight, stirring, filtering drying obtains 660 grams of crystal.Add it to 2000 milliliters of isopropanols, 1100 millis
Rise in alcohol mixed solution, be heated to 60 degree, crystal is completely dissolved, be cooled to room temperature, overnight, stir, filtering, a small amount of acetone is washed
Wash, drying obtains 510 grams of crystal.It is neutralized to alkalescence with 4M sodium hydroxide solutions, dichloromethane is extracted three times, dries concentration
Obtain 258.8 grams of colourless liquid, yield 32.7%.Specific rotation [a]=+ 24 (C1, CDCl3)；1H NMR(CDCl3,400MHz)
1.35(d,3H),1.47(bs,2H),4.09(q,1H),7.22(d,2H),7.44(d,2H)。
(3) preparation of the bromo- 3- methylisoindolines of (R) -6-
The bromo- α-phenylethylamines of 200g (R) -4- and 270g paraformaldehydes are dissolved in 3000 milliliters of glacial acetic acid, are added dropwise 30ml milliliters
Trifluoroacetic acid, the lower reaction 12 hours of 40 degree of reactant mixture.It is concentrated under reduced pressure, residue is dissolved in 3L ethyl acetate, saturated sodium carbonate
Solution is washed, and is washed, and is dried, is concentrated into 500 milliliters, and 2N ether hydrogen chloride solution stirring is slowly added dropwise under stirring, after 30 minutes,
Filtering, this step, which is not purified, directly carries out next step.
In order to be characterized to its structure, the product of the step is purified into the bromo- 3- methyl iso-indoles of (R) -6-
The product of the hydrochloride of quinoline, the nuclear-magnetism characterize data of structure is as follows：1H NMR(CDCl3,400MHz)1.57(d,3H),4.47
(dd,2H),4.82(m,1H),7.31(d,1H),7.58(d,1H),7.67(s,1H),9.86(s,1H),10.36(s,1H)。
(4) preparation of the bromo- 1- methylisoindolines of (R)-N-Boc-5-
150g (R) -6- bromo- 3- methylisoindolines (2000 milliliters) dissolvings of dichloromethane, while adding 4- diformazan ammonia
Yl pyridines 3g, stirring is lower to be added dropwise 196g Boc acid anhydrides, reacts at room temperature 3 hours.600 milliliters of saturated sodium bicarbonate solution is added,
Solid 3- alanine 30g are added, continue to stir 5 hours.Layering, organic phase dries concentration, residue with ethyl acetate and oil
Ether 15 to 1 is recrystallized, and obtains off-white powder 175g, yield 84%.1H NMR(CDCl3,400MHz)1.48(dd,3H),
1.57(s,9H),4.52-4.62(m,1H),4.62-4.76(m,1H),4.92-5.06(m,1H),7.42(dd,1H),7.35
(dd,1H),7.39(s,1H)。
Applicant states that the present invention illustrates that the bromo- 1- methyl of (R)-N-Boc-5- of the present invention is different by above-described embodiment
Indoline and its preparation method and application, but the invention is not limited in above-described embodiment, that is, do not mean that the present invention must be according to
Bad above-described embodiment could be implemented.Person of ordinary skill in the field is it will be clearly understood that any improvement in the present invention, to this hair
The equivalence replacement of bright each raw material of product and addition, the selection of concrete mode of auxiliary element etc., all fall within the protection model of the present invention
Within the scope of enclosing and disclosing.
Claims (10)
1. the preparation method of one kind bromo- 1- methylisoindolines of (R)-N-Boc-5-, it is characterised in that methods described includes following
Step：
(1) the bromo- α-phenylethylamines of (R) -4- lewis acid effect under with polyformaldehyde reaction, obtain the bromo- 1- methyl of (R) -5- different
Indoline, reaction equation is as follows：
(2) secondary amino group in the bromo- 1- methylisoindolines of (R) -5- is obtained into (R)-N-Boc-5- using tertbutyloxycarbonyl protection
Bromo- 1- methylisoindolines, reaction equation is as follows：
2. preparation method according to claim 1, it is characterised in that step (1) described lewis acid is dilute sulfuric acid, anhydrous
In zinc chloride, alchlor, trifluoroacetic acid, titanium tetrachloride or BFEE any one or at least two combination,
It is preferred that trifluoroacetic acid；
Preferably, the mol ratio of the bromo- α-phenylethylamines of (R) -4- described in step (1) and paraformaldehyde is 1:(1.5-3)；
Preferably, the temperature of step (1) described reaction is 20-60 DEG C.
3. preparation method according to claim 1 or 2, it is characterised in that the solvent of step (1) described reaction is ice vinegar
In acid, toluene, benzene or acetonitrile any one or at least two combination；
Preferably, the time of step (1) described reaction is 4-7 hours；
Preferably, step (1) reaction is carried out under protective gas protection, the preferred nitrogen of protective gas.
4. the preparation method according to any one of claim 1-3, it is characterised in that the bromo- α of (R) -4- described in step (1) -
Phenyl ethylamine is prepared by raw material of parabromoacetophenone；
Preferably, the preparation method of the bromo- α-phenylethylamines of (R) -4- comprises the following steps described in step (1)：
A, parabromoacetophenone and ammonium formate reaction obtain the bromo- phenyl ethylamines of 4-, and reaction equation is as follows：
B, using chiral resolving agent the bromo- phenyl ethylamines of 4- split obtaining the bromo- α-phenylethylamines of 4-, reaction equation is as follows：
5. preparation method according to claim 4, it is characterised in that parabromoacetophenone described in step A and ammonium formate rub
You are than being 1:3.5-1:6；
Preferably, the condition reacted described in step A is：Reacted 2-4 hours first at 110-130 DEG C, be then warming up to 170-
190 DEG C, react 4-10 hours.
6. the preparation method according to claim 4 or 5, it is characterised in that chiral resolving agent described in step B is D- almonds
In acid, D- tartaric acid or D- dibenzoyl tartaric acids any one or at least two combination；
Preferably, chiral resolving agent described in step B and the mol ratio of the bromo- phenyl ethylamines of 4- are (0.8-1.4):1, preferably 1:1；
Preferably, the solvent reacted described in step B is in isopropanol, ethanol, dimethylformamide or 1-METHYLPYRROLIDONE
Any one or at least two combination；
Preferably, the temperature reacted described in step B is 40-80 DEG C, preferably 60 DEG C.
7. the preparation method according to any one of claim 4-6, it is characterised in that step (2) is described bromo- by (R) -5-
The method that secondary amino group in 1- methylisoindolines is protected using tertbutyloxycarbonyl is：(R) the bromo- 1- methylisoindolines of -5- exist
The bromo- 1- methylisoindolines of (R)-N-Boc-5- are obtained in the presence of organic base with Boc anhydride reactions；
Preferably, the described bromo- 1- methylisoindolines of (R) -5- are 1 with the mol ratio of Boc acid anhydrides:(1-1.5)；
Preferably, the organic base is DMAP or the carbon -7- alkene of 1,8- diazabicylo 11；
Preferably, the described bromo- 1- methylisoindolines of (R) -5- are room with the temperature of Boc anhydride reactions in the presence of organic base
Temperature；
Preferably, the described bromo- 1- methylisoindolines of (R) -5- are 4- with the time of Boc anhydride reactions in the presence of organic base
6 hours.
8. the preparation method according to any one of claim 4-7, it is characterised in that the solvent of step (2) described reaction
For dichloromethane and/or chloroform.
9. the bromo- 1- methyl of (R)-N-Boc-5- that the preparation method according to any one of claim 1-8 is prepared is different
Indoline.
10. the bromo- 1- methylisoindolines of (R)-N-Boc-5- according to claim 9 answering in antibacterials preparation
With；
Preferably, the antibacterials are T-3811.
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| CN111718290A (en) * | 2020-07-22 | 2020-09-29 | 苏州爱玛特生物科技有限公司 | Synthesis method of multi-configuration isoindoline-1-carboxylic acid amino acid compound |
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| CN113429333A (en) * | 2021-07-08 | 2021-09-24 | 江苏法安德医药科技有限公司 | Synthesis method of gatifloxacin intermediate |
| CN113429333B (en) * | 2021-07-08 | 2022-03-04 | 江苏法安德医药科技有限公司 | Synthesis method of gatifloxacin intermediate |
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Denomination of invention: A (R) - n-boc-5-bromo-1-methylisoindoline and its preparation and Application Effective date of registration: 20200417 Granted publication date: 20180109 Pledgee: Anxin Agricultural Insurance Co., Ltd. Shanghai Minhang Branch Co. Pledgor: SHANGHAI BALMXY PHARMACEUTICAL Co.,Ltd. Registration number: Y2020310000010 |
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