CN116655543A - Preparation method of ulcerative colitis treatment medicine - Google Patents
Preparation method of ulcerative colitis treatment medicine Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 11
- 206010009900 Colitis ulcerative Diseases 0.000 title claims abstract description 10
- 201000006704 Ulcerative Colitis Diseases 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- -1 5- (dimethylamino) -2- (methylamino) benzoic acid Chemical compound 0.000 claims abstract description 23
- MRUDNSFOFOQZDA-UHFFFAOYSA-N 2,6-dichlorobenzoic acid Chemical compound OC(=O)C1=C(Cl)C=CC=C1Cl MRUDNSFOFOQZDA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 210000001503 joint Anatomy 0.000 claims abstract description 4
- 238000001308 synthesis method Methods 0.000 claims abstract 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 29
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
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- JBLIDPPHFGWTKU-UHFFFAOYSA-N 2,6-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=CC=C1Cl JBLIDPPHFGWTKU-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
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- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 description 2
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
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- GTVVZTAFGPQSPC-QMMMGPOBSA-N (2s)-2-azaniumyl-3-(4-nitrophenyl)propanoate Chemical compound OC(=O)[C@@H](N)CC1=CC=C([N+]([O-])=O)C=C1 GTVVZTAFGPQSPC-QMMMGPOBSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- 108010072135 Cell Adhesion Molecule-1 Proteins 0.000 description 1
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- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010041012 Integrin alpha4 Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
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- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
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- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
- C07D239/96—Two oxygen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a medicine methyl calicheat for treating ulcerative colitis, which comprises the following steps: step 1, reacting 5- (dimethylamino) -2- (methylamino) benzoic acid with N alpha-Boc-4-amino-L-phenylalanine methyl ester to obtain an intermediate compound, and removing the intermediate compound to obtain an intermediate 4- (6-dimethylamino-1-methylquinazoline-2, 4[1H,3H ] -diketone-3-yl) -L-phenylalanine methyl ester; and 2, carrying out butt joint reaction on the product obtained in the step 1 and 2,6 dichlorobenzoic acid to obtain the methyl calicheapest. Compared with the prior art, the novel synthesis method of the methyl calicheat has the advantages of obvious advantages, high yield, environmental friendliness, complete reaction and fewer byproducts.
Description
Technical Field
The invention belongs to the field of chemical drug synthesis, and particularly relates to a novel preparation method of a drug methyl calicheat (Carotegrast methyl) for treating ulcerative colitis.
Background
Inflammatory Bowel Disease (IBD) is a group of chronic inflammatory bowel diseases with an unknown mechanism of occurrence and etiology, mainly including Ulcerative Colitis (UC) and Crohn's Disease (CD). Genetic susceptibility, abnormal immunity of intestinal mucosa, abnormal intestinal microecology, external environment and the like are considered to be possible causative factors of IBD at present.
Traditional therapeutic agents for IBD include aminosalicylic acid formulations, corticosteroids and immunosuppressants, which have limited efficacy and numerous adverse effects. The occurrence of biological agents (such as infliximab, an anti-TNF-alpha agent) relieves the above conditions to a certain extent, but still has certain defects, the rate of induction and maintenance relief is less than 50%, and 20% of patients need to perform intestinal resection surgery after 2-5 years of administration, and the biological agents have serious infusion reactions and systemic infection adverse reactions.
Integrins are heterodimeric transmembrane receptors consisting of an alpha subunit and a beta subunit, play an important role in the proliferation, signal transduction and transport processes of immune cells, mediate the migration and homing of inflammatory cells specifically to the gastrointestinal tract, are novel targets for IBD treatment, and are effective therapeutic drugs for treating IBD. Monoclonal antibody integrin inhibitors have been marketed for many years, such as natalizumab and vedelizumab, however, monoclonal antibodies require long-term injection, have both infusion adverse reactions, immunogenicity and deficiencies in efficacy decline due to the occurrence of drug-resistant antibodies, and natalizumab increases the risk of Progressive Multifocal Leukoencephalopathy (PML). Methyl calicheat, month 6 of 2022, was used in japan for the treatment of moderate ulcerative colitis (limited to cases where the therapeutic effect was insufficient with 5-aminosalicylic acid formulations), opening the era of small molecule integrin inhibitors for IBD treatment.
Methyl calicheat (Carotegrast methyl) is an ester prodrug of an oral small molecule alpha 4 integrin inhibitor. The anti-inflammatory agent can simultaneously act on alpha 4 beta 1 and alpha 4 beta 7 heterodimer transmembrane receptors expressed on immune cells, inhibit interaction between alpha 4 beta 7 and intestinal endothelial cell mucosa addressen cell adhesion molecule-1 (MAdCAM-1) and interaction between alpha 4 beta 1 and vascular endothelial cell vascular cell adhesion molecule-1 (VCAM-1), and prevent inflammatory cells from transferring to intestinal lymphoid tissues, and has the same action mechanism as natalizumab.
The methyl calicheat is an oral small molecule integrin inhibitor for the first batch treatment of IBD, and can improve patient compliance and reduce the burden of medical workers. From the existing data, the treatment of UC by methylcalicheat can increase the clinical remission rate, response rate and mucosal healing rate. In the aspect of safety, the methyl calicheat has good tolerance, the serum half-life and the clearance time of the methyl calicheat are shorter than those of natalizumab, and the medicine can be cleared rapidly from the body, so that the PML safety can be improved, and no PML cases are found at present. The medicine will benefit the majority of patients.
Chinese academic name of methyl calicheat (Carotegrast methyl): methyl (2S) -2- (2, 6-dichlorobenzoylamino) -3- {4- [6- (dimethylamino) -1-methyl-2, 4-dioxo-1, 4-dihydroquinazolin-3 (2H) -yl]Phenyl } propanoate of the formula: c (C) 28 H 26 Cl 2 N 4 O 5 Dividing intoThe weight of the components is as follows: 569.44 CAS registry number 401905-67-7, having the chemical formula:
methyl Kataist (Carotegrast methyl)
Prior art document patent CN200480010615 reports the synthesis route 1 of methyl calicheat as follows:
in scheme 1 above, methyl calicheat is synthesized in 5 to 6 steps, wherein noble metal catalyst pt/C is used, and finally methylation reaction is performed, and overall yield is low due to long route.
The prior art document CN200780050294 reports two preparation methods of the key intermediate of methyl calicheat, formula a, as follows:
method one:
and a second method:
the method in the technical document prepares a compound of the formula a through 4 steps of reaction, and finally, methyl carbotaist is obtained through methylation reaction; the second method is to prepare a compound of the formula a through 2 steps of reaction, and the compound of the formula a is subjected to methylation reaction according to a route 1 to obtain the methyl calicheat. However, the problems of longer route and lower yield still exist. Therefore, it is necessary to develop a preparation method of methyl carbotai new with shorter route, safe and simple operation, low cost and environmental protection.
Disclosure of Invention
The invention provides a novel preparation method of a medicine methyl calicheat (Carotegrast methyl) for treating ulcerative colitis, which comprises the following specific routes:
step 1, reacting 5- (dimethylamino) -2- (methylamino) benzoic acid with N alpha-Boc-4-amino-L-phenylalanine methyl ester to obtain an intermediate (N-Boc-formula c compound), and removing Boc to obtain an intermediate 4- (6-dimethylamino-1-methylquinazoline-2, 4[1H,3H ] -dione-3-yl) -L-phenylalanine methyl ester (formula c compound);
step 2, intermediate 4- (6-dimethylamino-1-methyl quinazoline-2, 4[1H,3H ] -diketone-3-group) -L-phenylalanine methyl ester (compound of formula c) reacts with 2,6 dichlorobenzoic acid to obtain methyl carbotaist.
Wherein the starting material N α -Boc-4-amino-L-phenylalanine methyl ester was synthesized in the following manner.
The route of the invention is different from the synthetic route of the methylcartilaginous acid reported in the prior art document CN200480010615 and CN200780050294, and the invention provides a method for synthesizing the methylcartilaginous acid by using 1, 5- (dimethylamino) -2- (methylamino) benzoic acid and N α The new method for preparing the methyl calicheate by taking Boc-4-amino-L-phenylalanine methyl ester and 2, 6-dichlorobenzoic acid as starting materials through 2-step reaction has the advantages of low-cost and easily purchased starting materials, safe and simple operation, low cost, environmental friendliness and the like.
The step 1 of the invention adopts 1, 5- (dimethylamino) -2- (methylamino) benzoic acid and N α -Boc-4-amino-L-phenylalanine methyl ester, wherein 5- (dimethylamino) -2- (methylamino) benzoic acid has a methyl group introduced in advance, avoiding the methylation reaction in the last step; n (N) α The Boc-4-amino-L-phenylalanine methyl ester material adopts Boc group to protect primary amino, and avoids the generation of amino by-products, which is different from the prior artThe largest highlight of the surgical file.
In the reaction of the step 1, the initial raw material 1, 5- (dimethylamino) -2- (methylamino) benzoic acid is firstly cyclized with an acylating agent to generate intermediate 5-dimethylamino-N-methyl isatoic anhydride, and then the intermediate is further cyclized with the initial raw material N α -Boc-4-amino-L-phenylalanine methyl ester reaction to form intermediate N α -Boc-4- { 2-amino-5-dimethylaminobenzoylamino } -L-phenylalanine methyl ester, which is then cyclized with an acylating agent to form N α -Boc-4- (6-dimethylamino-1-methylquinazolin-2, 4[1H, 3H)]-diketone-3-yl) -L-phenylalanine methyl ester (compound of formula c), wherein the acylating agent used in the process is selected from triphosgene or carbonyl diimidazole, and can achieve better reaction effect.
The reaction solvent in the step 1 is selected from dimethylformamide or dimethylacetamide, the solvent can ensure the dissolution of main materials and products, and the homogeneous system reaction can ensure the smooth progress of the reaction. In the invention, any excessive main materials in the reaction of the step 1 can cause the increase of byproducts, the post treatment is difficult to be purified and removed, and a little excessive acylating agent is favorable for the two cyclization reactions, and finally, the 5- (dimethylamino) -2- (methylamino) benzoic acid and N are confirmed by optimization α The molar ratio of Boc-4-amino-L-phenylalanine methyl ester to acylating agent is 1:0.9-1.1:2-2.4, preferably 1:0.95-1.05:2.1-2.3, the reaction can be smoothly carried out, and the by-products can be controlled to be minimum.
The key conditions of the reaction in the step 1 in the invention are as follows: 5- (dimethylamino) -2- (methylamino) benzoic acid is reacted with half amount of N, N' -carbonyldiimidazole at 15-25deg.C for 2-3 hr, and then N is added α -Boc-4-amino-L-phenylalanine methyl ester is continuously reacted for 2-3 hours at the temperature of 60-70 ℃, the rest N, N' -carbonyl diimidazole is finally added, the reaction is continuously carried out for 8-10 hours at the temperature of 60-70 ℃, and the reaction conditions are controlled to ensure that the reaction is complete in each stage and the byproducts are fewer.
In the reaction of the step 2,6 dichlorobenzoic acid needs to react with an acylating agent firstly, and then is in butt joint with 4- (6-dimethylamino-1-methyl quinazoline-2, 4[1H,3H ] -diketone-3-yl) -L-phenylalanine methyl ester (a compound shown in a formula c), wherein the acylating agent is selected from thionyl chloride or carbonyl diimidazole; i tried other acylating conditions, such as DCC as the acylating agent, but the byproducts were more. And thionyl chloride or carbonyl diimidazole is adopted as an acylating agent, so that byproducts are fewer. However, when the acylating agent is thionyl chloride, an organic base is added as an acid-binding agent in the butt joint reaction, and the organic base is selected from N, N-diisopropylethylamine or triethylamine.
In the reaction in the step 2, when the acylating agent is thionyl chloride, the molar feed ratio of 4- (6-dimethylamino-1-methyl quinazoline-2, 4[1H,3H ] -diketone-3-yl) -L-phenylalanine methyl ester (compound of formula c), 2,6 dichlorobenzoic acid, thionyl chloride and organic base is 1:0.9-1.1:1-2: 1 to 3, preferably 1:0.95 to 1.05:1.2 to 1.8:1.5 to 2.5, particularly preferably 1:1:1.5:2, with fewer by-products.
In the step 2 reaction of the present invention, when the acylating agent is carbonyldiimidazole, 4- (6-dimethylamino-1-methylquinazolin-2, 4[1H,3H ] -dione-3-yl) -L-phenylalanine methyl ester (compound of formula c) is relatively expensive, and a small excess of 2, 6-dichlorobenzoic acid and acylating agent N, N '-carbonyldiimidazole are used to make 4- (6-dimethylamino-1-methylquinazolin-2, 4[1H,3H ] -dione-3-yl) -L-phenylalanine methyl ester (compound of formula c) react as completely as possible, and the excess materials are easy to remove, and finally, the molar ratio of 4- (6-dimethylamino-1-methylquinazolin-2, 4[1H,3H ] -dione-3-yl) -L-phenylalanine methyl ester (compound of formula c), 2, 6-dichlorobenzoic acid and N, N' -carbonyldiimidazole is confirmed to be 1:1-1.2, preferably 1.05-1.1:1.05, particularly preferably 1:1.15:1.15, and the optimal reaction effect is 1:1.15.
The key conditions in the step 2 reaction in the invention when the acylating agent is carbonyl diimidazole are as follows: 2,6 dichlorobenzoic acid reacts with N, N' -carbonyl diimidazole for 1-2 hours at the temperature of 15-25 ℃, and then 4- (6-dimethylamino-1-methyl quinazoline-2, 4[1H,3H ] -diketone-3-yl) -L-phenylalanine methyl ester is added for continuous reaction for 5-6 hours at the temperature of 50-60 ℃, so that the reaction can be ensured to be complete, and byproducts are fewer.
The invention provides a high-yield and environment-friendly preparation method of methyl calicheapest, which has obvious advantages compared with the prior art.
The specific implementation method comprises the following steps:
the technical solutions in the embodiments of the present invention will be described in detail in the following embodiments of the present invention, but the following embodiments are only for understanding the present invention, and are not limited to the present invention, which can be implemented in various ways defined and covered by the claims.
The novel synthesis of methylcartilast and the advantages of this method will be further described below in connection with examples 1-7 of the present invention. The method comprises the following steps:
examples 1 and N α -Boc-4-nitro-L-phenylalanine
Placing 4-nitro-L-phenylalanine (105.1 g, 0.5 mol), 300ml of water, 200ml of acetone and 100ml of 5mol/L sodium hydroxide aqueous solution in a three-mouth bottle, stirring and dissolving, slowly dropwise adding BOC anhydride (109.1 g, 0.5 mol) below 10 ℃ after controlling the temperature, continuously controlling the temperature to 15-25 ℃ after dropwise adding for reacting for 1h, adjusting ph to neutrality by 200ml of 5mol hydrochloric acid, precipitating solid, filtering, washing with water, and drying a filter cake to obtain N α Boc-4-nitro-L-phenylalanine (148.9 g, 96% yield), ms M/z 311.1 (M+1).
Example 2, N α -Boc-4-nitro-L-phenylalanine methyl ester
Will N α Placing (A) Boc-4-nitro-L-phenylalanine (124.0 g,0.4 mol), 300ml of water and 200ml of acetone in a three-mouth bottle, heating to 40-50 ℃ under stirring, controlling 160ml of Wen Dijia mol/L sodium hydroxide solution and dimethyl sulfate (50.4 g,0.4 mol), dropwise adding, continuing to react for 0.5h under control temperature, cooling to room temperature, adding 500ml of ethyl acetate, stirring and separating liquid, extracting water phase with 300ml of ethyl acetate, merging organic phases, washing with 500ml of water and 400ml of saturated sodium chloride in sequence, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to remove most of solvent, adding 200ml of normal hexane into the residue, stirring for dispersion, filtering, and drying filter cake to obtain N α -Boc-4-nitro-L-phenylalanine methyl ester107.6g, yield 83%), ms M/z 325.1 (M+1).
Example 3, N α -Boc-4-amino-L-phenylalanine methyl ester
Will N α Boc-4-nitro-L-phenylalanine (97.3 g, 0.3 mol), absolute ethanol 1000ml and 5% Pd/C (31.9 g,15 mmol) were placed in an autoclave, air was replaced, pressurized to 0.5-1MPa, reacted for 10h at 30-40℃under pressure, depressurized and filtered. Concentrating the filtrate to remove 4/5 solvent, cooling the residue, filtering, leaching the filter cake with ethanol, and oven drying the filter cake to obtain N α -Boc-4-amino-L-phenylalanine methyl ester (71.5 g,81%, purity 98.2%), ms M/z 295.2 (M+1). 1 HNMR(300MHz d 6 -DMSO)：δ1.45(s，9H)，3.67(s，3H)，2.88～3.13(m，2H)，4.70(t，1H),6.46(d，2H)，6.94(d，2H)，7.40(d，1H)。
EXAMPLE 4 Synthesis of 4- (6-dimethylamino-1-methylquinazolin-2, 4[1H,3H ] -dione-3-yl) -L-phenylalanine methyl ester (Compound of formula c) 1
5- (dimethylamino) -2- (methylamino) benzoic acid (38.8 g,0.2 mol), N' -carbonyldiimidazole (35.6 g,0.22 mol) and dimethylformamide (250 ml) were added to a three-necked flask, and the reaction was carried out at 15-25℃for 3 hours; adding N α -Boc-4-amino-L-phenylalanine methyl ester (58.8 g,0.2 mol), continuously reacting for 2 hours at the temperature of 60-70 ℃, adding N, N' -carbonyldiimidazole (CDI, 35.6g,0.22 mol), continuously reacting for 10 hours at the temperature of 60-70 ℃, cooling to room temperature, adding 300ml of water and 300ml of dichloromethane, stirring and separating liquid, extracting the aqueous phase with 300ml of dichloromethane, merging organic phases, washing the organic phases with 300ml of saturated saline solution, and separating liquid; adding trifluoroacetic acid (25.1 g,0.22 mol) into the organic phase, stirring at room temperature for 2 hr, adding water 300ml, adjusting pH to 7-8 with 10% sodium bicarbonate solution, separating, washing the organic phase with water 300ml, adding anhydrous sulfuric acid into the organic phaseDrying sodium 30g for 2h, filtering, concentrating the filtrate under reduced pressure to dryness, adding absolute ethanol 400ml into the residue, heating to reflux for dissolution, naturally cooling to room temperature for crystallization, filtering, and vacuum drying the filter cake to obtain the title compound 4- (6-dimethylamino-1-methylquinazoline-2, 4[1H, 3H)]-diketone-3-yl) -L-phenylalanine methyl ester (compound of formula c, 65.0g, yield 82%, chemical purity 98.6%). Ms M/z 397.2 (M+1). 1 HNMR(300MHz d 6 -DMSO): delta 3.10 (s, 6H), 3.16 and 3.44 (m, 2H), 3.68 (s, 3H), 3.91 (s, 3H), 4.15 (t, 1H), 7.16 (d, 1H), 7.19 (d, 2H), 7.33 (d, 2H), 7.38 (s, 1H), 7.52 (m, 1H).
EXAMPLE 5 Synthesis of 4- (6-dimethylamino-1-methylquinazolin-2, 4[1H,3H ] -dione-3-yl) -L-phenylalanine methyl ester (Compound of formula c) 2
150ml of 5- (dimethylamino) -2- (methylamino) benzoic acid (19.4 g,0.1 mol), triphosgene (BTC, 32.6g,0.11 mol) and dimethylacetamide were added to a three-necked flask, and the reaction was controlled at 15-25℃for 2 hours; adding N α -Boc-4-amino-L-phenylalanine methyl ester (29.4 g,0.1 mol), continuing to react for 2 hours at the temperature of 60-70 ℃, adding triphosgene (BTC, 32.6,0.112 mol), continuing to react for 8 hours at the temperature of 60-70 ℃, cooling to room temperature, adding 150ml of water and 200ml of dichloromethane, stirring and separating liquid, extracting the aqueous phase with 150ml of dichloromethane, merging organic phases, washing with 150ml of saturated saline water, and separating liquid; adding trifluoroacetic acid (12.5 g,0.11 mol) into the organic phase, stirring at room temperature for 2h, adding 150ml of water, adjusting pH to 7-8 with 10% sodium bicarbonate solution, separating, washing the organic phase with 150ml of water again, adding 10g of anhydrous sodium sulfate into the organic phase, drying for 2h, filtering, concentrating the filtrate under reduced pressure to dryness, adding 200ml of absolute ethanol into the residue, heating to reflux for dissolution, naturally cooling to room temperature for crystallization, filtering, and vacuum drying the filter cake to obtain the title compound 4- (6-dimethylamino-1-methylquinazoline-2, 4[1H, 3H)]-diketone-3-yl) -L-phenylalanine methyl ester (compound of formula c, 31.3g, yield 79%, chemical purity 97.8%), ms M/z 397.2 (m+1).
EXAMPLE 6 Synthesis of Methylcalicheapest 1
2, 6-dichlorobenzoic acid (21.0 g,0.11 mol), N, N' -carbonyldiimidazole (CDI, 17.8g,0.11 mol) and dimethylformamide (120 ml) were added to a three-necked flask, the reaction was conducted at 15-25℃for 1-2 hours, and then 4- (6-dimethylamino-1-methylquinazoline-2, 4[1H, 3H) was added]-diketone-3-yl) -L-phenylalanine methyl ester (formula c,39.6g,0.1 mol), heating to 50-60 ℃ for continuous reaction for 6h, cooling to room temperature, adding 300ml of water to precipitate a large amount of solid, filtering, washing filter cake, and drying filter cake to obtain methyl carbotaist (47.3 g, yield 83%, chemical purity 99.1%, optical purity 99.5%). Ms M/z 569.2 (M+1), 1 H NMR(300MHz d 6 -DMSO)：δ2.92(s，6H)，3.00(q，1H)，3.20(q，1H)，3.45(s，3H)，3.68(s，3H)，4.80(m，1H)，7.13-7.18(m，2H)，7.21(d，1H)，7.28(q，1H)，7.33-7.45(m，6H)，9.28(d，1H)。
EXAMPLE 7 Synthesis of Methylcalicheapest 2
2, 6-dichlorobenzoic acid (7.0 g,50 mmmol) and 50ml of methylene chloride were added to a three-necked flask, thionyl chloride (8.9 g,75 mmol) was slowly added dropwise thereto, the reaction was carried out under reflux for 1 hour, the solvent was evaporated under reduced pressure, and the residue was dissolved in 30ml of methylene chloride to prepare a methylene chloride solution of 2, 6-dichlorobenzoyl chloride.
Methyl 4- (6-dimethylamino-1-methylquinazolin-2, 4[1H,3H ] -dione-3-yl) -L-phenylalanine (compound of formula c, 19.8g,50 mmol), triethylamine (10.1 g,0.1 mol) and 60ml of dichloromethane were added to a three-necked flask, cooled to below 10 ℃, dropwise added with a dichloromethane solution of 2, 6-dichlorobenzoyl chloride at below 10 ℃ under control of temperature, the reaction was continued at room temperature for 2h after the dropwise addition, 100ml of 5% sodium bicarbonate solution was added, the solution was separated with stirring, the organic phase was washed with 100ml of water, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, the residue was added with 50ml of absolute ethanol, filtered, the filter cake was washed with water, and the filter cake was dried to give methylcalicheastat (21.62 g, yield 76%, chemical purity 98.8%, optical purity 99.3%) Ms M/z 569.2 (M+1).
Compared with the prior art, the method has the advantages that the yield is higher, the health damage to production operators is reduced, and the method is more environment-friendly.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (7)
1. A preparation method of a drug for treating ulcerative colitis, namely methyl calicheat, which is characterized by comprising the following steps:
step 1, 5- (dimethylamino) -2- (methylamino) benzoic acid and N α The reaction of (E) -Boc-4-amino-L-phenylalanine methyl ester firstly obtains intermediate (N-Boc-compound of formula c), and then obtains intermediate 4- (6-dimethylamino-1-methyl quinazoline-2, 4[1H, 3H) through deboc]-diketone-3-yl) -L-phenylalanine methyl ester (compound of formula c);
step 2, intermediate 4- (6-dimethylamino-1-methyl quinazoline-2, 4[1H,3H ] -diketone-3-group) -L-phenylalanine methyl ester (compound of formula c) and 2,6 dichlorobenzoic acid are subjected to butt joint reaction to obtain methyl carbotaist.
2. The synthesis according to claim 1, wherein the starting material N α -Boc-4-amino-L-phenylalanine methyl ester was synthesized by:
3. the synthesis according to claim 1, wherein step 1 is carried out with the addition of an acylating agent selected from triphosgene or carbonyldiimidazole, preferably carbonyldiimidazole.
4. A synthetic method according to claim 1 or 3, wherein in the step 1 reaction 5- (dimethylamino) -2- (methylamino) benzoic acid, N α The molar feed ratio of the Boc-4-amino-L-phenylalanine methyl ester to the acylating agent is 1:0.9-1.1:2-2.4, preferably 1:0.95-1.05:2.1-2.3.
5. The method of claim 1, wherein 2,6 dichlorobenzoic acid is reacted with an acylating agent selected from thionyl chloride or carbonyldiimidazole in the step 2 reaction followed by 4- (6-dimethylamino-1-methylquinazolin-2, 4[1h,3h ] -dione-3-yl) -L-phenylalanine methyl ester (compound of formula c).
6. The method according to claim 1 and 5, wherein when the acylating agent is thionyl chloride, an acid-binding agent organic base is added for the docking reaction, and the organic base is selected from N, N-diisopropylethylamine or triethylamine.
7. The synthesis method according to claim 1, 5 and 6, wherein when the acylating agent is thionyl chloride, the molar feed ratio of 4- (6-dimethylamino-1-methylquinazolin-2, 4[1h,3h ] -dione-3-yl) -L-phenylalanine methyl ester (compound of formula c), 2,6 dichlorobenzoic acid, thionyl chloride, organic base is 1:0.9-1.1:1-2: 1 to 3, preferably 1:0.95 to 1.05:1.2 to 1.8:1.5 to 2.5, particularly preferably 1:1:1.5:2.
The synthesis according to claims 1 and 5, wherein when the acylating agent is carbonyldiimidazole, the molar feed ratio of 4- (6-dimethylamino-1-methylquinazoline-2, 4[1h,3h ] -diketo-3-yl) -L-phenylalanine methyl ester (compound of formula b), 2,6 dichlorobenzoic acid and N, N' -carbonyldiimidazole is 1:1 to 1.2:1 to 1.2, preferably 1:1.05 to 1.15:1.05 to 1.15, particularly preferably 1:1.1:1.1.
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