CN104045606B - One kettle way prepares the method for Ah examining for amine hydrochlorate - Google Patents
One kettle way prepares the method for Ah examining for amine hydrochlorate Download PDFInfo
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- 150000001412 amines Chemical class 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 238000006482 condensation reaction Methods 0.000 claims abstract description 4
- 238000000926 separation method Methods 0.000 claims abstract description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000012317 TBTU Substances 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical group C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 6
- 238000004176 ammonification Methods 0.000 claims description 5
- CURJNMSGPBXOGK-UHFFFAOYSA-N n',n'-di(propan-2-yl)ethane-1,2-diamine Chemical compound CC(C)N(C(C)C)CCN CURJNMSGPBXOGK-UHFFFAOYSA-N 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 2
- 239000007821 HATU Substances 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 6
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 2
- KVZUCOGWKYOPID-UHFFFAOYSA-N 2,4,5-Trimethoxybenzoic acid Chemical compound COC1=CC(OC)=C(C(O)=O)C=C1OC KVZUCOGWKYOPID-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 238000013517 stratification Methods 0.000 description 4
- 230000009435 amidation Effects 0.000 description 3
- 238000007112 amidation reaction Methods 0.000 description 3
- 201000006549 dyspepsia Diseases 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- -1 phenyl ester Chemical class 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 3
- HWFCHCRFQWEFMU-UHFFFAOYSA-N 2-bromo-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(Br)=C(C(O)=O)C=C1OC HWFCHCRFQWEFMU-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 206010013786 Dry skin Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000003292 diminished effect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- RFLGFUHTFLSIKA-UHFFFAOYSA-N 1,3-thiazole-4-carboxamide trihydrate hydrochloride Chemical compound O.O.O.Cl.NC(=O)C1=CSC=N1 RFLGFUHTFLSIKA-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RUBXSZYVSFYJQR-UHFFFAOYSA-N 2-hydroxy-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(O)=C(C(O)=O)C=C1OC RUBXSZYVSFYJQR-UHFFFAOYSA-N 0.000 description 1
- DAUAQNGYDSHRET-UHFFFAOYSA-N 3,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OC DAUAQNGYDSHRET-UHFFFAOYSA-N 0.000 description 1
- TWHZNAUBXFZMCA-UHFFFAOYSA-N Acotiamide Chemical compound C1=C(OC)C(OC)=CC(O)=C1C(=O)NC1=NC(C(=O)NCCN(C(C)C)C(C)C)=CS1 TWHZNAUBXFZMCA-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 0 COC(C1=NC(N)=S*1)=O Chemical compound COC(C1=NC(N)=S*1)=O 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229950005462 acotiamide Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- KUWWRNNYEYGSBQ-UHFFFAOYSA-N methyl 1,3-thiazole-4-carboxylate Chemical class COC(=O)C1=CSC=N1 KUWWRNNYEYGSBQ-UHFFFAOYSA-N 0.000 description 1
- KOPRMBXEMNEOOQ-UHFFFAOYSA-N methyl 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylate Chemical class COC(=O)C1=CSC(NC(=O)C=2C(=CC(OC)=C(OC)C=2)O)=N1 KOPRMBXEMNEOOQ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- XZZNDPSIHUTMOC-UHFFFAOYSA-N triphenyl phosphate Chemical group C=1C=CC=CC=1OP(OC=1C=CC=CC=1)(=O)OC1=CC=CC=C1 XZZNDPSIHUTMOC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of one kettle way and prepare the method for Ah examining for amine hydrochlorate (compound V), the method is with 2 shown in formula (I), thiazolamine-4-methyl-formiate shown in 4,5-trimethoxybenzoic acid and formula (II) is raw material, obtains compound III through condensation reaction; By selecting suitable solvent and controlling reaction conditions, intermediate III is without separation and purification, directly and the N shown in formula (IV), N-diisopropyl ethylenediamine carries out aminating reaction, and last salify one kettle way prepares Ah examining for amine hydrochlorate (compound V), the present invention's one kettle way prepares Ah examining for amine hydrochlorate, decrease reactions steps, simplify operating process, improve production efficiency, and safety and environmental protection, be applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to the preparation method technical field of Ah examining for amine hydrochlorate.
Background technology
Ah examining is for amine (acotiamide); chemistry N-{2 by name-[two (1-methylethyl) is amino] ethyl }-2-[(2-hydroxyl-4; 5-Dimethoxybenzoyl) amino] thiazole-4-carboxamide hydrochloride trihydrate; developed by AstraZeneca (Astellas) pharmacy and Ze Li new drug K.K. Union; treatment functional dyspepsia (FD) is approved in Japan on June 6th, 2013; first FD medicine in the world; there is good curative effect, have no drug resistance and show high security.
Ah the examining that prepare that current document is reported mainly contains following several for the method for amine hydrochlorate (compound V):
Route one: (1. WO2012077673(CN103237781 A) (2011))
Route one for starting raw material, obtains 2-BROMO-4,5-DIMETHOXYBENZOIC ACID through bromination, hydrolysis with 4,5-dimethoxybenzoic acid.Then react with thiazolamine-4-methyl-formiate again after 2-BROMO-4,5-DIMETHOXYBENZOIC ACID being converted into corresponding phenyl ester and generate 2-(2-hydroxyl-4,5-dimethoxybenzamido) 4-thiazolecarboxylic acid methyl esters.2-(2-hydroxyl-4,5-dimethoxybenzamido) the further ammonification of 4-thiazolecarboxylic acid methyl esters, salify obtain Ah examining for amine hydrochlorate.This overall yield of reaction of bibliographical information reaches 85%, but when the first step carries out bromination, needs to use concentrated hydrochloric acid and the larger bromine of toxicity in a large number, and it is also more to react issuable by product; In addition this route multistep has used toluene, need carry out the repeatedly transfer of steaming except toluene and material, operate more loaded down with trivial details, be unfavorable for suitability for industrialized production.
Route two: (2.CN102040566B(2005))
Route two for starting raw material, obtains 2-hydroxyl-4,5-dimethoxybenzoic acid by the selectivity methyl sloughed on 2 methoxyl groups with 2,4,5-trimethoxybenzoic acid.2-hydroxyl-4,5-dimethoxybenzoic acid phenyl ester is obtained again through over-churning.Further amidation and transesterify can obtain product Ah examining for amine hydrochlorate.The total recovery of this route bibliographical information is 75%, but the method step is more.This route adopts boron trifluoride diethyl etherate simultaneously, and aftertreatment is more loaded down with trivial details.In addition, use triphenylphosphate Atom economy poor, reagent boric acid ester price is more expensive, and these factors make this route economy poor.
Route three: (3.CN1184471A(1996))
This route for starting raw material, prepares Ah examine for amine hydrochlorate through amidation, selectivity demethylation and ammonification three step with 2,4,5-trimethoxybenzoic acid.The method total recovery only has 35%, there is no advantage compared with other method, and needs the pyridine that use toxicity is larger.
Route four: (4.CN1084739C(1998))
Route four is the most succinct and yield is higher, and it for starting raw material, prepares Ah examine for amine hydrochlorate through amidation and ammonification two step with 2,4,5-trimethoxybenzoic acid.But there is following shortcoming in this route: 1. used sulfur oxychloride in preparation process, sulfurous gas and hydrogenchloride can be produced, equipment and workman's protection are had higher requirements, also can produce certain environmental problem; 2. the preparation of acyl chlorides is subject to ambient moisture and sulfur oxychloride quality influence comparatively large, and operational requirement is relatively high; 3. employ kind solvent 1, a 2-ethylene dichloride; 4. need to carry out repeatedly material transfer.And the compound III often first separation and purification in this route, then carry out next step reaction, make industrial operation loaded down with trivial details.The present invention, by selecting suitable solvent and controlling reaction conditions etc., is not separated this intermediate, and directly " one kettle way " prepares Ah examining for amine hydrochlorate, greatly simplify technological operation, improves production efficiency.Meanwhile, the present invention TBTU substitutes sulfur oxychloride, not only avoid the pollution using acyl chlorides to bring, and avoids repeatedly material transfer, thus enhances productivity, and is conducive to carrying out continuous industrial production.
Summary of the invention
The object of the present invention is to provide a kind of simple process, safety and environmental protection, be suitable for the preparation method of Ah examining for amine hydrochlorate of suitability for industrialized production.
In order to realize foregoing invention object, present invention employs a kind of one kettle way and preparing the method for Ah examining for amine hydrochlorate, the following technical scheme of concrete employing:
A kind of one kettle way prepares formula V
Shown Ah examining, for the method for amine hydrochlorate, is characterized in that, by formula (I)
Shown compound and formula (II)
Shown compound is heat condensation in the solvent of condensing agent and alkali, obtains formula (III)
Shown compound, compound (III) without separation, with formula (IV)
Shown compound ammonification, finally uses hydrogenchloride salify, obtains Ah examining for amine hydrochlorate (compound V).
A kind of one kettle way prepares the method for Ah examining for amine hydrochlorate, it is characterized in that, with DMF or DMAc for reaction solvent, under the existence of condensing agent and alkali, with 2 shown in formula (I), after thiazolamine-4-methyl-formiate shown in 4,5-trimethoxybenzoic acid and formula (II) carries out condensation reaction, then shown in adding type (IV)
n, N-diisopropyl ethylenediamine carries out aminating reaction, and last salify one kettle way prepares Ah examining for amine hydrochlorate (compound V).
One kettle way prepares the method for Ah examining for amine hydrochlorate, it is characterized in that, the mol ratio of Compound I and Compound II per is 1:1.0 ~ 2.0, is preferably 1:1.1 ~ 1.5.The mol ratio of Compound I and condensing agent is 1:1.0 ~ 3.0, is preferably 1:1.0 ~ 1.5.The molar ratio of Compound I and compound IV is 1:1.0 ~ 5.0, preferred 1:2.0 ~ 4.0.
Described a kind of one kettle way prepares the method for Ah examining for amine hydrochlorate, and condensing agent can be selected from salt TBTU, HATU, HBTU, TSTU, is preferably TBTU.Setting-up point is 55-105 DEG C, and be preferably 70-90 DEG C, the reaction times is 6-24 hour.
Described a kind of one kettle way prepares the method for Ah examining for amine hydrochlorate, it is characterized in that, described alkali is organic bases, and wherein organic bases can be selected from diisopropylethylamine, triethylamine, pyridine, is preferably diisopropylethylamine.
Described a kind of one kettle way prepares the method for Ah examining for amine hydrochlorate, and aminating reaction temperature is 120-150 DEG C, preferred 130-140 DEG C; Reaction times is 4-10 hour.
Specific operation process of the present invention is as follows: with 2 shown in formula (I), 4, thiazolamine-4-methyl-formiate shown in 5-trimethoxybenzoic acid and formula (II) is raw material, under the effect of condensing agent and alkali, there is condensation reaction, then with DMF or DMAc for reaction solvent, add shown in formula (IV)
n,N-diisopropyl ethylenediamine carries out aminating reaction, finally uses hydrogenchloride salify, obtains Ah examining for amine hydrochlorate (compound V).
Compared with prior art, the present invention has following beneficial effect: 1, overcome industrial operation in prior art loaded down with trivial details, is unsuitable for the shortcoming of suitability for industrialized production.2, adopt one kettle way to prepare Ah examining for amine hydrochlorate, greatly simplifie operating process, improve production efficiency.3, safety and environmental protection, environmental pollution is less.
Embodiment
Come by the following examples to describe the present invention in more detail, but this should not regard limitation of the present invention as.
Example 1: Ah examining is for the preparation of amine hydrochlorate
2,4,5-trimethoxybenzoic acid (20 g, 94.3mmol) is added, 200 ml DMFs in 500ml reaction flask.Add TBTU(30.88 g, 113.2mmol), add
n,N-diisopropylethylamine (14.59g, 113.2mmol), at room temperature stirs 2 hours.Add thiazolamine-4-methyl-formiate (14.92 g, 94.3mmol), DMAP(2.30g, 18.9mmol), be heated to 75 DEG C, stir 24 hours.Add
n,N-diisopropyl ethylenediamine (27.16g, 188.6mmol), is heated to 140 DEG C, stirs 10 hours.After cooling, add 400ml propyl carbinol, stir, stratification.Get upper strata, wash with saturated aqueous common salt 400ml, stratification.Get upper strata, under low temperature, drip hydrogenchloride Virahol 120ml, separate out solid.Filtration under diminished pressure, air dry oven 60 DEG C of dryings 1 hour put into by filter cake.Get A Kao replaces amine hydrochlorate (compound V) 28.5g, HPLC purity 99%, yield 62%.
1H NMR (400 MHz, dmso) δ 12.10 (s, 1H), 11.77 (s, 1H), 9.74 (s, 1H), 8.72 (t,
J= 5.8 Hz, 1H), 7.88 (s, 1H), 7.48 (s, 1H), 6.89 (s, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.62 (d,
J= 6.6 Hz, 4H), 3.16 (d,
J= 6.4 Hz, 2H), 1.32 (dd,
J= 13.4, 6.3 Hz, 12H)。
Example 2: Ah examining is for the preparation of amine hydrochlorate
2,4,5-trimethoxybenzoic acid (20g, 94.3mmol) is added, 200ml in 500ml reaction flask
n,N-N,N-DIMETHYLACETAMIDE.Add TBTU(30.88g, 113.2mmol), add
n,N-diisopropylethylamine (14.59g, 113.2mmol)), at room temperature stir 2 hours.Add thiazolamine-4-methyl-formiate (14.92g, 94.3mmol), DMAP(2.3g, 18.9mmol), be heated to 75 DEG C, stir 24 hours.Add
n,N-diisopropyl ethylenediamine (27.16g, 188.6mmol), is heated to 140 DEG C, stirs 10 hours.After cooling, add 400ml propyl carbinol, stir, stratification.Get upper strata, wash with saturated aqueous common salt 400ml, stratification.Get upper strata, drip hydrogenchloride Virahol 120ml under low temperature, separate out solid, filtration under diminished pressure, air dry oven 60 DEG C of dryings 1 hour put into by filter cake.Get A Kao replaces amine hydrochlorate (compound V) 31.7 g, HPLC purity 99%, yield 69%.
Claims (9)
1. an one kettle way prepares formula V
Shown Ah examining, for the method for amine hydrochlorate, is characterized in that, by formula (I)
Shown compound and formula (II)
Shown compound is under the existence of condensing agent and alkali, and heat condensation in a solvent, obtains formula (III)
Shown compound, compound III without separation, with formula (IV)
Shown compound ammonification, finally uses hydrogenchloride salify, obtains Ah examining for amine hydrochlorate (compound V); Wherein said condensing agent is TBTU, HATU, HBTU or TSTU.
2. preparation method according to claim 1, it is characterized in that, with DMF or DMAc for reaction solvent, under the existence of condensing agent and alkali, with 2 shown in formula (I), after thiazolamine-4-methyl-formiate shown in 4,5-trimethoxybenzoic acid and formula (II) carries out condensation reaction, then shown in adding type (IV)
n,N-diisopropyl ethylenediamine carries out aminating reaction, and last salify one kettle way prepares Ah examining for amine hydrochlorate (compound V).
3. according to preparation method according to claim 1 or claim 2, it is characterized in that, the mol ratio of Compound I and Compound II per is 1:1.1 ~ 1.5; The mol ratio of Compound I and condensing agent is 1:1 ~ 1.5.
4. according to preparation method according to claim 1 or claim 2, it is characterized in that, setting-up point is 55 ~ 105 DEG C, and the reaction times is 6 ~ 24 hours.
5. preparation method according to claim 4, is characterized in that setting-up point is 70 ~ 90 DEG C.
6. according to preparation method according to claim 1 or claim 2, it is characterized in that, described alkali is diisopropylethylamine, triethylamine or pyridine.
7. according to preparation method according to claim 1 or claim 2, it is characterized in that, the molar ratio of Compound I and compound IV is 1:1.0 ~ 5.0.
8. preparation method according to claim 7, is characterized in that, the molar ratio of Compound I and compound IV is 1:2.0 ~ 4.0.
9. according to preparation method according to claim 1 or claim 2, it is characterized in that, aminating reaction temperature is 120 ~ 150 DEG C; Reaction times is 4 ~ 10 hours.
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| CN104698106B (en) * | 2015-03-21 | 2016-06-29 | 石家庄四药有限公司 | A kind of chemicals acotiamide hydrochloride hydrate has the detection method of related substance |
| CN105439978B (en) * | 2015-12-15 | 2018-02-16 | 山东金城医药化工股份有限公司 | The preparation method of Acotiamide intermediate |
| CN106316979B (en) * | 2016-08-22 | 2018-11-27 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of acotiamide hydrochloride hydrate |
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