CN108395413B - A kind of preparation method of morpholine -3- carboxylic acid - Google Patents
A kind of preparation method of morpholine -3- carboxylic acid Download PDFInfo
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Abstract
The present invention provides a kind of preparation methods of morpholine -3- carboxylic acid; the preparation method includes obtaining the morpholine -3- carboxylic acid by Michael addition reaction, deprotection reaction, cyclization reaction and hydrolysis using N- tertiary butyloxycarbonyl ethylethanolamine and 2- chloroacrylonitrile as raw material；The preparation method of morpholine -3- carboxylic acid provided by the present invention; morpholine -3- carboxylic acid is obtained by Michael's addition, deprotection, cyclization and hydrolysis, whole preparation process is simple, and step is few; raw material is cheap and easy to get; it is non-stimulated without easy allergy object in reaction process, it avoids generating hypertoxicity product and by-product, the yield of every single step reaction can reach 80% or more; total recovery is high; be conducive to be mass produced, promote economic benefit, have good market value.
Description
Technical field
The invention belongs to medicine intermediates to synthesize field, be related to a kind of preparation method of morpholine -3- carboxylic acid.
Background technique
Morpholine -3- carboxylic acid is a kind of important medicine intermediate, is had a wide range of applications in medical synthesis field.Currently,
Existing synthetic method mainly has following two lines:
The morpholine that first route is protected using tertbutyloxycarbonyl (Boc) is raw material, by etherification reaction, cyanogenation, water
Solution reaction and nitrogen protection finally obtain product, and specific reaction equation is as follows:
But there are the condition of first step reaction is more demanding in this route, reaction is not easily controlled, and yield is lower, the
Trimethylsilyl cyanide is used in the reaction of two steps, this reagent, which meets water, can generate the hydrogen cyanide of severe toxicity, and there are biggish security risks, therefore
This route is unfavorable for production operation.
Article 2 route using N- benzyl serine as raw material, by acylation reaction, cyclization reaction, reduction hydrogenation and
The replacement of nitrogen-protecting group, oxidation reaction finally obtain target product, and specific reaction equation is as follows:
But the step of this route, is long, total recovery is lower, and the reduction reaction of third step, uses borine to carry out anti-
It answers, does not meet the theory of Green Chemistry.
CN102617503A discloses a kind of new synthetic method of (S)-morpholinyl carboxylic acid, reacts and is produced by 5 steps
Object: (1) using Serine as Material synthesis L-serine tert-butyl ester；(2) L-serine tert-butyl ester is dissolved in methylene chloride, is dripped
The dichloromethane solution of chlorination chloroacetic chloride obtains N- chloracetyl-L-serine tert-butyl ester；(3) by N- chloracetyl-Serine
The tert-butyl ester is dissolved in toluene solution, and the toluene solution of sodium ethoxide is added dropwise, and obtains (S) -5- oxo morpholinyl carboxylic acid tert-butyl ester；(4)
(S) -5- oxo morpholinyl carboxylic acid tert-butyl ester is dissolved in methanol, alchlor successively is added and sodium borohydride is reacted,
Obtain (S)-morpholinyl carboxylic acid tert-butyl ester；(5) (S)-morpholinyl carboxylic acid tert-butyl ester is dissolved in methanol, the first of hydrogen chloride is added dropwise
Alcoholic solution reacts (S)-morpholinyl carboxylic acid.This preparation method is related equally to using sodium borohydride reduction, and in reaction
Using arrive chloracetyl chloride, it is unfriendly to environment.
All there are some defects in the preparation method being currently known, therefore, how to develop a kind of new preparation method, both had
Have a high income, easy to operate, but it is environmentally friendly, cost is relatively low the characteristics of, for producing and moving towards market with important meaning
Justice.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of morpholine -3- carboxylic acid.
To achieve this purpose, the present invention adopts the following technical scheme:
The present invention provides a kind of preparation method of morpholine -3- carboxylic acid, the preparation method includes with N- tertbutyloxycarbonyl
Ethanol amine and 2- chloroacrylonitrile are raw material, are obtained by Michael addition reaction, deprotection reaction, cyclization reaction and hydrolysis
Morpholine -3- the carboxylic acid.
The preparation method of morpholine -3- carboxylic acid provided by the invention, it is anti-by Michael's addition, deprotection, cyclization and hydrolysis
Morpholine -3- carboxylic acid should be obtained, whole preparation process is simple, and step is few, and raw material is cheap and easy to get, non-stimulated without easy mistake in reaction process
Quick object avoids generating hypertoxicity product and by-product, and the yield of every single step reaction can reach 80% or more, and total recovery is high.
And that there are routes is longer, reaction generates hypertoxic product, reduction reaction has the defects of pollution for existing method, especially
The certain reaction yields being related in individual routes only have more than 60% (such as prepare morpholine -3- carboxylic acid by raw material of Serine,
Serine is 65%) yield of Material synthesis L-serine tert-butyl ester only has in first step reaction, even lower, is influenced final
The yield of product is unfavorable for production preparation.
Preferably, the preparation method specifically includes the following steps:
(1) by N- tertiary butyloxycarbonyl ethylethanolamine (N-Boc- ethanol amine) and 2- chloroacrylonitrile condition existing for catalyst
Under, it carries out Michael addition reaction and obtains [2 (the chloro- 2- cyano-ethyoxyl of 2-) ethyl] t-butyl carbamate, specific reaction equation
It is as follows:
(2) [2 (the chloro- 2- cyano-ethyoxyl of 2-) ethyl] t-butyl carbamate that step (1) obtains is dissolved in solvent
In, deprotection reaction is carried out using hydrochloric acid and obtains 3- (2- amino ethoxy) -2- chloroethyl nitrile hydrochloride, and specific reaction equation is as follows:
(3) 3- (2- the amino ethoxy) -2- chloroethyl nitrile hydrochloride condition existing for acid binding agent obtained step (2)
Under, it carries out cyclization reaction and obtains morpholine -3- first cyanogen, specific reaction equation is as follows:
(4) reaction is hydrolyzed in the morpholine -3- first cyanogen that step (3) obtains in acid condition and obtains the morpholine -3-
Carboxylic acid, specific reaction equation are as follows:
Preferably, catalyst described in step (1) includes trimethyl-phosphine, triethyl phosphine, tributylphosphine, triphenylphosphine, carbon
Sour potassium, sodium carbonate, cesium carbonate, 11 carbon -7- alkene of 1,8- diazabicylo, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, hydrogen-oxygen
Change potassium, benzyltrimethylammonium hydroxide, tetraethyl ammonium hydroxide, tetramethylammonium hydroxide, sodium hydride, hydrofining, butyl lithium, second
In sodium alkoxide, sodium methoxide, Sodamide or lithium diisopropylamine any one or at least two combination, preferably trimethyl
Phosphine.
Preferably, the molar ratio of N- tertiary butyloxycarbonyl ethylethanolamine described in step (1) and 2- chloroacrylonitrile is 1:1.05-
1.2, such as can be 1:1.05,1:1.08,1:1.1,1:1.13,1:1.15 or 1:1.2.
Preferably, relative to the N- tertiary butyloxycarbonyl ethylethanolamine of 1mol, the dosage of the catalyst is 0.4-0.8, such as
It can be 0.4,0.5,0.6,0.65,0.7,0.72,0.75,0.78 or 0.8.
Preferably, solvent used in Michael addition reaction described in step (1) includes acetonitrile, ether or tetrahydrofuran
In any one.
Preferably, the temperature of Michael addition reaction described in step (1) is 40-60 DEG C, such as can be 40 DEG C, 45
DEG C, 50 DEG C, 52 DEG C, 53 DEG C, 55 DEG C, 58 DEG C or 60 DEG C.
Preferably, the time of Michael addition reaction described in step (1) be 20-30h, such as can be 20h, 21h,
22h, 23h, for 24 hours, 25h, 27h, 28h, 29h or 30h.
Preferably, Michael addition reaction described in step (1) carries out under conditions of protective gas is protected.
Preferably, the protective gas include in nitrogen, argon gas or helium any one or at least two combination,
Preferably nitrogen.
In the present invention, oxa- Michael addition reaction is used in step (1), high income can reach 80% or more, after being
The convenience that continuous reaction provides, so that subsequent reactions only need to carry out simple deprotection reaction and hydrolysis etc. can to prepare
Target product, compared to using N- benzyl serine, N-Boc morpholine and Serine as the method for raw material, yield is higher, without multiple
Miscellaneous operation, the generation of the hypertoxic product avoided, more conducively large-scale production operation.
Preferably, solvent described in step (2) is Isosorbide-5-Nitrae-dioxane or ethyl acetate, preferably Isosorbide-5-Nitrae-dioxane.
Preferably, in step (2), relative to faint yellow solid described in 1mol, the dosage of solvent is 200-500mL, such as
It can be 200mL, 250mL, 300mL, 350mL, 400mL, 450mL or 500mL.
Preferably, the volume ratio of hydrochloric acid described in step (2) and solvent is 1:1-2, such as can be 1:1,1:1.1,1:
1.2,1:1.3,1:1.4,1:1.5,1:1.6,1:1.7,1:1.8,1:1.9 or 1:2.
Preferably, the concentration of hydrochloric acid described in step (2) be 4-7M, such as can be 4M, 4.5M, 5M, 5.5M, 6M,
6.5M or 7M.
Preferably, the temperature of deprotection reaction described in step (2) is 0-10 DEG C, such as can be 0 DEG C, 1 DEG C, 2 DEG C, 3
DEG C, 4 DEG C, 5 DEG C, 6 DEG C, 7 DEG C, 8 DEG C, 9 DEG C or 10 DEG C.
Preferably, the time of deprotection reaction described in step (2) be 1-4h, such as can be 1h, 1.5h, 2h, 2.5h,
3h, 3.5h or 4h.
Preferably, acid binding agent described in step (3) includes in potassium carbonate, cesium carbonate, sodium bicarbonate, pyridine or triethylamine
Any one or at least two combination.
Preferably, the molar ratio of white powder described in step (3) and acid binding agent is 1:2.5-4, such as can be 1:
2.5,1:2.7,1:2.8,1:3,1:3.1,1:3.3,1:3.5,1:3.8 or 1:4.
Preferably, the solvent of cyclization reaction described in step (3) is tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, water or acetic acid second
In ester any one or at least two combination, preferably tetrahydrofuran and water composition mixed solvent.
Preferably, the temperature of cyclization reaction described in step (3) be 30-60 DEG C, such as can be 30 DEG C, 35 DEG C, 40 DEG C,
45 DEG C, 50 DEG C, 55 DEG C or 60 DEG C.
Preferably, the time of cyclization reaction described in step (3) be 3-6h, such as can be 3h, 3.5h, 4h, 4.5h,
5h, 5.5h or 6h.
Preferably, acid condition described in step (4) is provided by inorganic acid.
Preferably, the inorganic acid includes concentrated hydrochloric acid or the concentrated sulfuric acid；
Preferably, relative to the morpholine -3- first cyanogen of 1mol, the dosage of the inorganic acid is 800mL-1000mL, such as can
To be 800mL, 850mL, 880mL, 900mL, 920mL, 950mL, 980mL or 1000mL.
Preferably, the temperature of hydrolysis described in step (4) be 60-90 DEG C, such as can be 60 DEG C, 65 DEG C, 70 DEG C,
75 DEG C, 80 DEG C, 85 DEG C or 90 DEG C.
Preferably, the time of hydrolysis described in step (4) be 5-8h, such as can be 5h, 5.5h, 6h, 6.5h,
7h, 7.5h or 8h.
In the present invention, the morpholine -3- carboxylic acid of step (4) preparation exists in the form of inorganic acid salt.
The preparation method route of morpholine -3- carboxylic acid provided by the invention is as follows:
Compared with the existing technology, the invention has the following advantages:
The preparation method of morpholine -3- carboxylic acid provided by the invention, it is anti-by Michael's addition, deprotection, cyclization and hydrolysis
Morpholine -3- carboxylic acid should be obtained, whole preparation process is simple, and step is few, and raw material is cheap and easy to get, non-stimulated without easy mistake in reaction process
Quick object avoids generating hypertoxicity product and by-product, and the yield of every single step reaction can reach 80% or more, and total recovery is high, has
Conducive to large-scale production, there is economic benefit and market value.
Specific embodiment
The technical scheme of the invention is further explained by means of specific implementation.Those skilled in the art should be bright
, the described embodiments are merely helpful in understanding the present invention, should not be regarded as a specific limitation of the invention.
Embodiment 1
(1) it is reacted with N-Boc- ethanol amine with 2- chloroacrylonitrile starting material, specific reaction equation is as follows:
N-Boc- ethanol amine (161g, 1mol) is added in acetonitrile (1L), is added 2- chloroacrylonitrile (92g, 1.05mol),
Nitrogen replaces system three times, is added with stirring trimethyl-phosphine (38g, 0.5mol), and system is warming up to 50 DEG C, and it is small persistently to stir 25
When, it filters, concentration, 500mL water is added, ethyl acetate extracts 2 times, merges organic phase, and dry, concentration obtains faint yellow solid
206g, yield 83%.
1H NMR(CDCl3,400MHz):δ6.52(s,1H),4.65(dd,1H),4.03(ddd,2H),3.47-3.55(m,
2H),3.02-3.13(m,2H),1.46(s,9H)。
(2) deprotection reaction is carried out using hydrochloric acid, specific reaction equation is as follows:
The faint yellow solid (190g, 0.76mol) that step (1) obtains is dissolved in Isosorbide-5-Nitrae-dioxane (200mL), ice bath,
Isosorbide-5-Nitrae-dioxane (1.5L) of 3M and the hydrochloric acid 1.5L of 6M is added dropwise, after continuing stirring 2 hours, is added dropwise ether (800mL), mistake
Filter, drying obtain white powder 112g, and product is direct plungeed into and reacted in next step by thick yield 80%.
(3) it carries out cyclization reaction and prepares morpholine -3- first cyanogen, specific reaction equation is as follows:
The white powder (112g, 0.6mol) that step (2) obtains is dissolved in tetrahydrofuran and the mixed system (2L) of water 1:1
In, ice bath stirs lower dropwise addition potassium carbonate (248g, 1.8mol), and the system of dripping off is warming up to 40 DEG C, persistently stirs 5 hours.Layering,
Water phase ethyl acetate extracts 2 times, merges the organic phase of tetrahydrofuran and ethyl acetate, dry, concentration, residue with ethyl acetate and
The mixed solvent crystallization of petroleum ether 1:1 obtains class white powder end 60g, yield 90%.
1H NMR(CDCl3,400MHz):δ3.92-3.73(m,4H),3.64-3.58(m,1H),3.24-3.17(m,1H),
2.77(ddd,1H),2.14(s,1H)。
(4) morpholine -3- carboxylic acid hydrochloride is prepared, specific reaction equation is as follows:
Morpholine -3- first the cyanogen (50g, 0.44mol) that step 3 obtains is dissolved in the hydrochloric acid of 6M (400mL), system is warming up to
80 DEG C and stirring 6 hours.Reaction is cooled to 5 DEG C, stirs 1 hour, and filtering acetone washing 3 times, obtains pale powder 60g,
Quinoline -3- carboxylic acid hydrochloride, yield 82%.
1H NMR(400MHz,DMSO-d6)δ8.48(s,2H),3.95(dd,1H),3.74(ddd,1H),3.64-3.48
(m,3H),3.14(ddd,1H),2.98(ddd,1H)。
Embodiment 2
(1) it is reacted with N-Boc- ethanol amine with 2- chloroacrylonitrile starting material, specific reaction equation is as follows:
N-Boc- ethanol amine (161g, 1mol) is added in acetonitrile (1L), is added 2- chloroacrylonitrile (105g, 1.2mol),
Nitrogen replaces system three times, is added with stirring sodium ethoxide (27.22g, 0.4mol), and system is warming up to 40 DEG C, and it is small persistently to stir 30
When, it filters, concentration, 500mL water is added, ethyl acetate extracts 2 times, merges organic phase, and dry, concentration obtains faint yellow solid
200g, yield 80.6%.
1H NMR(CDCl3,400MHz):δ6.52(s,1H),4.65(dd,1H),4.03(ddd,2H),3.47-3.55(m,
2H),3.02-3.13(m,2H),1.46(s,9H)。
(2) deprotection reaction is carried out using hydrochloric acid, specific reaction equation is as follows:
The faint yellow solid (190g, 0.76mol) that step (1) obtains is dissolved in Isosorbide-5-Nitrae-dioxane (152mL), ice bath,
Isosorbide-5-Nitrae-dioxane (1.5L) of 3M and the hydrochloric acid 0.75L of 7M is added dropwise, after continuing stirring 1 hour, is added dropwise ether (800mL), mistake
Filter, drying obtain white powder 109g, and product is direct plungeed into and reacted in next step by thick yield 77.5%.
(3) it carries out cyclization reaction and prepares morpholine -3- first cyanogen, specific reaction equation is as follows:
The white powder (109g, 0.58mol) that step (2) obtains is dissolved in the mixed system of tetrahydrofuran and water 1:1
In (2L), ice bath stirs lower dropwise addition cesium carbonate (472.4g, 1.45mol), and the system of dripping off is warming up to 30 DEG C, and it is small persistently to stir 6
When.Layering, water phase ethyl acetate extract 2 times, merge the organic phase of tetrahydrofuran and ethyl acetate, dry, concentration, residue second
The mixed solvent crystallization of acetoacetic ester and petroleum ether 1:1 obtains class white powder end 58g, yield 89.3%.
1H NMR(CDCl3,400MHz):δ3.92-3.73(m,4H),3.64-3.58(m,1H),3.24-3.17(m,1H),
2.77(ddd,1H),2.14(s,1H)。
(4) morpholine -3- carboxylic acid hydrochloride is prepared, specific reaction equation is as follows:
Morpholine -3- first the cyanogen (50g, 0.44mol) that step 3 obtains is dissolved in the hydrochloric acid of 6M (352mL), system is warming up to
60 DEG C and stirring 8 hours.Reaction is cooled to 5 DEG C, stirs 1 hour, and filtering acetone washing 3 times, obtains pale powder 58.1g,
Morpholine -3- carboxylic acid hydrochloride, yield 79.4%.
1H NMR(400MHz,DMSO-d6)δ8.48(s,2H),3.95(dd,1H),3.74(ddd,1H),3.64-3.48
(m,3H),3.14(ddd,1H),2.98(ddd,1H)。
Embodiment 3
(1) it is reacted with N-Boc- ethanol amine with 2- chloroacrylonitrile starting material, specific reaction equation is as follows:
N-Boc- ethanol amine (161g, 1mol) is added in acetonitrile (1L), is added 2- chloroacrylonitrile (92g, 1.05mol),
Nitrogen replaces system three times, is added with stirring potassium tert-butoxide (89.8g, 0.8mol), and system is warming up to 60 DEG C, and it is small persistently to stir 20
When, it filters, concentration, 500mL water is added, ethyl acetate extracts 2 times, merges organic phase, and dry, concentration obtains faint yellow solid
195g, yield 78.6%.
1H NMR(CDCl3,400MHz):δ6.52(s,1H),4.65(dd,1H),4.03(ddd,2H),3.47-3.55(m,
2H),3.02-3.13(m,2H),1.46(s,9H)。
(2) deprotection reaction is carried out using hydrochloric acid, specific reaction equation is as follows:
The faint yellow solid (190g, 0.76mol) that step (1) obtains is dissolved in Isosorbide-5-Nitrae-dioxane (380mL), ice bath,
Isosorbide-5-Nitrae-dioxane (1.5L) of 3M and the hydrochloric acid 1.5L of 4M is added dropwise, after continuing stirring 4 hours, is added dropwise ether (800mL), mistake
Filter, drying obtain white powder 105g, and product is direct plungeed into and reacted in next step by thick yield 74.6%.
(3) it carries out cyclization reaction and prepares morpholine -3- first cyanogen, specific reaction equation is as follows:
The white powder (100g, 0.54mol) that step (2) obtains is dissolved in the mixed system of tetrahydrofuran and water 1:1
In (2L), ice bath stirs lower dropwise addition potassium carbonate (297.6g, 1.8mol), and the system of dripping off is warming up to 60 DEG C, persistently stirs 3 hours.
Layering, water phase ethyl acetate extract 2 times, merge the organic phase of tetrahydrofuran and ethyl acetate, dry, concentration, residue acetic acid
The mixed solvent crystallization of ethyl ester and petroleum ether 1:1 obtains class white powder end 55g, yield 90.8%.
1H NMR(CDCl3,400MHz):δ3.92-3.73(m,4H),3.64-3.58(m,1H),3.24-3.17(m,1H),
2.77(ddd,1H),2.14(s,1H)。
(4) morpholine -3- carboxylic acid sulfate is prepared, specific reaction equation is as follows:
Morpholine -3- first the cyanogen (50g, 0.44mol) that step 3 obtains is dissolved in the sulfuric acid of 4M (440mL), system is warming up to
90 DEG C and stirring 5 hours.Reaction is cooled to 5 DEG C, stirs 1 hour, and filtering acetone washing 3 times, obtains pale powder 53g,
Quinoline -3- carboxylic acid sulfate, yield 72.4%.
1H NMR(400MHz,DMSO-d6)δ8.48(s,2H),3.95(dd,1H),3.74(ddd,1H),3.64-3.48
(m,3H),3.14(ddd,1H),2.98(ddd,1H)。
The Applicant declares that the preparation method of the present invention is explained by the above embodiments morpholine -3- carboxylic acid of the invention, but
The invention is not limited to above-mentioned method detaileds, that is, do not mean that the invention must rely on the above detailed methods to implement.Institute
Belong to those skilled in the art it will be clearly understood that any improvement in the present invention, to the equivalence replacement of each raw material of product of the present invention
And addition, selection of concrete mode of auxiliary element etc., all of which fall within the scope of protection and disclosure of the present invention.
Claims (26)
1. a kind of preparation method of morpholine -3- carboxylic acid inorganic acid salt, which is characterized in that the preparation method includes with the tertiary fourth oxygen of N-
Carbonyl ethanol amine and 2- chloroacrylonitrile are raw material, by Michael addition reaction, deprotection reaction, cyclization reaction and hydrolysis
Obtain the morpholine -3- carboxylic acid inorganic acid salt；
The preparation method specifically includes the following steps:
(1) under the conditions of by N- tertiary butyloxycarbonyl ethylethanolamine and 2- chloroacrylonitrile existing for the catalyst, it is anti-to carry out Michael's addition
[2- (the chloro- 2- cyano-ethyoxyl of 2-) ethyl] t-butyl carbamate should be obtained, specific reaction equation is as follows:
(2) [2- (the chloro- 2- cyano-ethyoxyl of 2-) ethyl] t-butyl carbamate that step (1) obtains is dissolved in solvent,
Deprotection reaction is carried out using hydrochloric acid and obtains 3- (2- amino ethoxy) -2- chloroethyl nitrile hydrochloride, and specific reaction equation is as follows:
(3) under the conditions of 3- (2- the amino ethoxy) -2- chloroethyl nitrile hydrochloride obtained step (2) is existing for the acid binding agent, into
Row cyclization reaction obtains morpholine -3- first cyanogen, and specific reaction equation is as follows:
(4) reaction is hydrolyzed in the morpholine -3- first cyanogen that step (3) obtains in acid condition and obtains the morpholine -3- carboxylic acid
Inorganic acid salt, specific reaction equation are as follows:
Catalyst described in step (1) is trimethyl-phosphine；
Acid binding agent described in step (3) is for any one in potassium carbonate, cesium carbonate, sodium bicarbonate, pyridine or triethylamine or extremely
Few two kinds of combination.
2. according to power require 1 described in preparation method, which is characterized in that N- tertiary butyloxycarbonyl ethylethanolamine described in step (1) with
The molar ratio of 2- chloroacrylonitrile is 1:1.05-1.2.
3. the preparation method according to weighing and require 1, which is characterized in that relative to the N- tertiary butyloxycarbonyl ethylethanolamine of 1mol, step
Suddenly the dosage of (1) described catalyst is 0.4-0.8mol.
4. the preparation method according to weighing and require 1, which is characterized in that Michael addition reaction described in step (1) is used
Solvent include any one in acetonitrile, ether or tetrahydrofuran.
5. the preparation method according to weighing and require 1, which is characterized in that the temperature of Michael addition reaction described in step (1)
It is 40-60 DEG C.
6. the preparation method according to weighing and require 1, which is characterized in that the time of Michael addition reaction described in step (1)
For 20-30h.
7. the preparation method according to weighing and require 1, which is characterized in that Michael addition reaction described in step (1) is being protected
It is carried out under conditions of property gas shield.
8. the preparation method according to weighing and require 7, which is characterized in that the protective gas is in nitrogen, argon gas or helium
Any one or at least two combination.
9. the preparation method according to weighing and require 8, which is characterized in that the protective gas is nitrogen.
10. according to power require 1 described in preparation method, which is characterized in that solvent described in step (2) be Isosorbide-5-Nitrae-dioxane or
Ethyl acetate.
11. the preparation method according to weighing and require 10, which is characterized in that solvent described in step (2) is Isosorbide-5-Nitrae-dioxane.
12. the preparation method according to weighing and require 1, which is characterized in that relative to [2- (the chloro- 2- cyano-second of 2- described in 1mol
Oxygroup) ethyl] t-butyl carbamate, the dosage of solvent is 200-500mL.
13. according to power require 1 described in preparation method, which is characterized in that the volume ratio of hydrochloric acid described in step (2) and solvent is
1:1-2。
14. the preparation method according to weighing and require 1, which is characterized in that the concentration of hydrochloric acid described in step (2) is 4-7M.
15. the preparation method according to weighing and require 1, which is characterized in that the temperature of deprotection reaction described in step (2) is 0-
10℃。
16. the preparation method according to weighing and require 1, which is characterized in that the time of deprotection reaction described in step (2) is 1-
4h。
17. the preparation method according to weighing and require 1, which is characterized in that 3- described in step (3) (2- amino ethoxy) -2-
The molar ratio of chloroethyl nitrile hydrochloride and acid binding agent is 1:2.5-4.
18. the preparation method according to weighing and require 1, which is characterized in that the solvent of cyclization reaction described in step (3) is tetrahydro
In furans, 1,4- dioxane, water or ethyl acetate any one or at least two combination.
19. the preparation method according to weighing and require 18, which is characterized in that the solvent of cyclization reaction described in step (3) is four
The mixed solvent of hydrogen furans and water composition.
20. the preparation method according to weighing and require 1, which is characterized in that the temperature of cyclization reaction described in step (3) is 30-
60℃。
21. the preparation method according to weighing and require 1, which is characterized in that the time of cyclization reaction described in step (3) is 3-
6h。
22. the preparation method according to weighing and require 1, which is characterized in that acid condition described in step (4) is mentioned by inorganic acid
For.
23. the preparation method according to weighing and require 22, which is characterized in that the inorganic acid is concentrated hydrochloric acid or the concentrated sulfuric acid.
24. the preparation method according to weighing and require 22 or 23, which is characterized in that described relative to the morpholine -3- first cyanogen of 1mol
The dosage of inorganic acid is 800mL-1000mL.
25. the preparation method according to weighing and require 1, which is characterized in that the temperature of hydrolysis described in step (4) is 60-
90℃。
26. the preparation method according to weighing and require 1, which is characterized in that the time of hydrolysis described in step (4) is 5-
8h。
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