CN117024315A - Preparation method of (R) -5- (2-aminopropyl) -2-methoxyl benzenesulfonamide - Google Patents
Preparation method of (R) -5- (2-aminopropyl) -2-methoxyl benzenesulfonamide Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- -1 2-aminopropyl Chemical group 0.000 title abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 92
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 40
- 238000002156 mixing Methods 0.000 claims abstract description 38
- 239000003960 organic solvent Substances 0.000 claims abstract description 31
- IORITYIZDHJCGT-SSDOTTSWSA-N 5-[(2r)-2-aminopropyl]-2-methoxybenzenesulfonamide Chemical compound COC1=CC=C(C[C@@H](C)N)C=C1S(N)(=O)=O IORITYIZDHJCGT-SSDOTTSWSA-N 0.000 claims abstract description 17
- 239000003999 initiator Substances 0.000 claims abstract description 15
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 14
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 14
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000006722 reduction reaction Methods 0.000 claims abstract description 11
- 238000004176 ammonification Methods 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 claims description 35
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 28
- 239000000047 product Substances 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 239000012074 organic phase Substances 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 15
- 229910052763 palladium Inorganic materials 0.000 claims description 14
- 238000000926 separation method Methods 0.000 claims description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 11
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 238000004321 preservation Methods 0.000 claims description 10
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical group BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 239000011630 iodine Substances 0.000 claims description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- 230000001681 protective effect Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- HTDQSWDEWGSAMN-UHFFFAOYSA-N 1-bromo-2-methoxybenzene Chemical compound COC1=CC=CC=C1Br HTDQSWDEWGSAMN-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 23
- 238000003756 stirring Methods 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000012265 solid product Substances 0.000 description 7
- ZZIZZTHXZRDOFM-UHFFFAOYSA-N 2-(2-ethoxyphenoxy)ethyl-[1-(4-methoxy-3-sulfamoylphenyl)propan-2-yl]azanium;chloride Chemical compound Cl.CCOC1=CC=CC=C1OCCNC(C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-UHFFFAOYSA-N 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 229960003198 tamsulosin hydrochloride Drugs 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- WFWKNGZODAOLEO-UHFFFAOYSA-N 1-(4-Methoxyphenyl)-2-propanone Chemical compound COC1=CC=C(CC(C)=O)C=C1 WFWKNGZODAOLEO-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- RPPNACKXIUVYEF-VIFPVBQESA-N benzyl (4s)-4-methyl-5-oxo-1,3-oxazolidine-3-carboxylate Chemical group C1OC(=O)[C@H](C)N1C(=O)OCC1=CC=CC=C1 RPPNACKXIUVYEF-VIFPVBQESA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000012263 liquid product Substances 0.000 description 2
- 230000027939 micturition Effects 0.000 description 2
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000001256 steam distillation Methods 0.000 description 2
- 210000003708 urethra Anatomy 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- FMQVVEZTVJUUFQ-CQSZACIVSA-N benzyl n-[(2r)-1-(4-methoxyphenyl)propan-2-yl]carbamate Chemical group C1=CC(OC)=CC=C1C[C@@H](C)NC(=O)OCC1=CC=CC=C1 FMQVVEZTVJUUFQ-CQSZACIVSA-N 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
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- RBWRWAUAVRMBAC-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical group [Mg+2].[Br-].COC1=CC=[C-]C=C1 RBWRWAUAVRMBAC-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- GZGJIACHBCQSPC-UHFFFAOYSA-N methyl 3-chloropropanoate Chemical compound COC(=O)CCCl GZGJIACHBCQSPC-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- RUVINXPYWBROJD-UHFFFAOYSA-N para-methoxyphenyl Natural products COC1=CC=C(C=CC)C=C1 RUVINXPYWBROJD-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- ZZIZZTHXZRDOFM-XFULWGLBSA-N tamsulosin hydrochloride Chemical group [H+].[Cl-].CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-XFULWGLBSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- RUVINXPYWBROJD-ONEGZZNKSA-N trans-anethole Chemical compound COC1=CC=C(\C=C\C)C=C1 RUVINXPYWBROJD-ONEGZZNKSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of (R) -5- (2-aminopropyl) -2-methoxyl benzenesulfonamide. Mixing bromoanisole, magnesium metal, an initiator and an organic solvent to perform a first-stage format reaction, mixing the obtained first-stage format reaction liquid with a compound with a structure shown in a formula 2 to perform a second-stage format reaction, performing chlorosulfonation reaction on the obtained compound with a structure shown in a formula 3, mixing the obtained chlorosulfonation reaction liquid with ammonia water to perform an ammonification reaction, and performing a reduction reaction on the obtained compound with a structure shown in a formula 4 in a hydrogen atmosphere to obtain (R) -5- (2-aminopropyl) -2-methoxybenzene sulfonamide. The preparation method provided by the invention simplifies the operation flow, has less three wastes, has high yield in each step, and the obtained (R) -5- (2-aminopropyl) -2-methoxyl benzenesulfonamide product has high purity and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of (R) -5- (2-aminopropyl) -2-methoxyl benzenesulfonamide.
Background
Tamsulosin hydrochloride (tamsulosin hydrochloride), chemical name is R- (+) -5- [2- [ [2- (2-ethoxyphenoxy) ethyl ] amino ] propyl ] -2-methoxybenzenesulfonamide hydrochloride. The composition can selectively act on alpha 1 receptor in prostate and urethra smooth muscle, reduce internal pressure of urethra, and has low adverse side effect under therapeutic dose. Is suitable for treating frequent urination, difficult urination and the like caused by prostatic hyperplasia, has definite curative effect and low toxic and side effects, and is the optimal therapeutic drug for clinically benign prostatic hyperplasia. Tamsulosin hydrochloride has the following structure:
in the preparation process of tamsulosin hydrochloride, (R) -5- (2-aminopropyl) -2-methoxybenzene sulfonamide is a key intermediate for synthesizing tamsulosin hydrochloride, and the structural formula is as follows:
in tamsulosin hydrochloride synthesis (Du Hongguang, li Ming et al chemical reagents, 2007,29 (9), 541-543.) it is reported that (R) -5- (2-aminopropyl) -2-methoxybenzenesulfonamide is mainly obtained from p-methoxyphenylacetone by chlorosulfonation, ammoniation, asymmetric reductive amination of carbonyl and reductive debenzylation, and the reaction scheme is as follows:
the preparation process of the p-methoxyphenylacetone, which is a starting material used in the above synthetic route, is reported in "Hass synthesis ofpyridine and related compounds" (FerdW, hoover, henry b.. J.org. chem,1947,12,501-505.), and the p-methoxyphenylformaldehyde is specifically used as a starting material, and is obtained by condensation with nitroethane, reduction with iron/hydrochloric acid, hydrolysis, and steam distillation, wherein the reaction route is as follows:
the nitroethane adopted by the route is easy to make and explode, has potential safety hazard in industrial production, has the total yield of only 36 percent, also needs to be purified by adopting a steam distillation mode, has large three wastes and is not suitable for industrial production.
The journal of pharmacy (volume sixty-three, eighteen of Sho-A, 63,376-80.) reports that 1-methoxy-4- (prop-1-en-1-yl) benzene is used as a starting material and is obtained through the steps of bromine addition, hydrolysis, epoxidation and ring-opening oxidation, wherein the reaction route is as follows:
the epoxide prepared by the synthetic route reported in the journal of pharmacy needs to react at 180-220 ℃, has high equipment requirement, has no yield report in literature, and is not suitable for industrial production.
"Purifying and stabilizing alkoxy phenyl-oropan-a-ons" (Haene, randolf, albert, frank michael., ger (East) DD,206,77.) reported the preparation of p-methoxybenzaldehyde as a starting material by the reaction with 3-chloropropionic acid methyl ester using the Daqin reaction scheme as follows:
the above-mentioned route needs to adopt hydrochloric acid hydrolysis decarboxylation after condensation under the condition of sodium methoxide, the reaction condition is tedious, purify by way of rectifying, and the total yield is only 65%, unsuitable for the industrialized production.
In summary, the current synthetic route of (R) -5- (2-aminopropyl) -2-methoxybenzene sulfonamide is calculated from the preparation source of the p-methoxyphenylacetone serving as a starting material, has the problems of long synthetic route and low yield, and is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of (R) -5- (2-aminopropyl) -2-methoxyl benzenesulfonamide, which simplifies the operation steps, has less three wastes and high yield of each step, and the obtained (R) -5- (2-aminopropyl) -2-methoxyl benzenesulfonamide has high purity and is suitable for industrial production.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of (R) -5- (2-aminopropyl) -2-methoxyl benzenesulfonamide, which comprises the following steps:
(1) Mixing p-bromoanisole, magnesium metal, an initiator and an organic solvent to perform a first-stage format reaction to obtain a first-stage format reaction solution; the first-stage format reaction liquid contains a format product with a structure shown in a formula 1; mixing the first-stage format reaction liquid with a compound with a structure shown in a formula 2 to perform a second-stage format reaction to obtain a compound with a structure shown in a formula 3;
(2) Mixing chlorosulfonic acid with a compound with a structure shown in a formula 3 for chlorosulfonation reaction, and mixing the obtained chlorosulfonation reaction solution with ammonia water for ammoniation reaction to obtain a compound with a structure shown in a formula 4;
(3) In the atmosphere of hydrogen, the compound with the structure shown in the formula 4, an organic solvent and a palladium catalyst are mixed for reduction reaction to obtain (R) -5- (2-aminopropyl) -2-methoxybenzene sulfonamide.
Preferably, the mass ratio of the p-bromoanisole to the metal magnesium is 1:0.1 to 0.2; the mass ratio of the p-bromoanisole to the compound with the structure shown in the formula 2 is 1:1 to 2.
Preferably, the initiator is 1, 2-dibromoethane and iodine; the mass ratio of the 1, 2-dibromoethane to the iodine is 1:0.2-0.3; the mass ratio of the p-bromoanisole to the initiator is 1: 0.004-0.005.
Preferably, in step (1), the first stage format reaction includes the steps of: in the atmosphere of protective gas, mixing part of organic solvent, part of p-bromoanisole, metal magnesium and initiator for pre-reaction to obtain pre-reaction liquid; mixing the pre-reaction liquid, the residual para-bromoanisole and the residual organic solvent, and continuing to react under the condition of reflux to obtain a format reaction liquid; the mass ratio of part of the para-bromoanisole to the rest of the para-bromoanisole is 1:24, a step of detecting the position of the base; the temperature of the pre-reaction is 30-35 ℃, and the heat preservation time is 30-60 min.
Preferably, in the step (1), after the second-stage format reaction is finished, a second-stage format reaction solution is obtained, and the second-stage format reaction solution contains a first intermediate; the chemical structural formula of the first intermediate is as follows:
mixing the second-stage format reaction solution with hydrochloric acid, and separating the solution to obtain an organic phase and a water phase; extracting the aqueous phase with a first organic solvent, and combining the obtained extracted organic phase with an organic phase obtained by liquid separation to obtain an organic phase product, wherein the organic phase product contains a second intermediate, and the chemical structural formula of the second intermediate is as follows:
and mixing the organic phase product, trifluoroacetic acid and triethylsilane for reaction to obtain the compound with the structure shown in the formula 3.
Preferably, the temperature of the second stage format reaction is 0-70 ℃ and the time is 1-2 days.
Preferably, the mass ratio of the compound with the structure shown in the formula 3 to chlorosulfonic acid is 1:5 to 15; the temperature of chlorosulfonation reaction and ammonification reaction is independently 0-80 ℃.
Preferably, the ammonification reaction is carried out to obtain an ammonification reaction liquid, and the method further comprises the steps of cooling the ammonification reaction liquid, carrying out heat preservation crystallization and solid-liquid separation to obtain a compound with a structure shown in a formula 4; the temperature of the heat preservation crystallization is 0-30 ℃ and the time is 1-24 h.
Preferably, the palladium catalyst is palladium carbon, and the mass content of palladium in the palladium carbon is 5-10%;
the mass ratio of the compound with the structure shown in the formula 4 to the palladium catalyst is 1:0.01 to 0.5.
Preferably, the pressure of the hydrogen is 0.01-2 MPa.
The invention provides a preparation method of (R) -5- (2-aminopropyl) -2-methoxyl benzenesulfonamide, which comprises the following steps: (1) Mixing p-bromoanisole, magnesium metal, an initiator and an organic solvent to perform a first-stage format reaction to obtain a first-stage format reaction solution; the first-stage format reaction liquid contains a format product with a structure shown in a formula 1; mixing the first-stage format reaction liquid with a compound with a structure shown in a formula 2 to perform a second-stage format reaction to obtain a compound with a structure shown in a formula 3; (2) Mixing chlorosulfonic acid with a compound with a structure shown in a formula 3 for chlorosulfonation reaction, and mixing the obtained chlorosulfonation reaction solution with ammonia water for ammoniation reaction to obtain a compound with a structure shown in a formula 4; (3) In the atmosphere of hydrogen, the compound with the structure shown in the formula 4, an organic solvent and a palladium catalyst are mixed for reduction reaction to obtain (R) -5- (2-aminopropyl) -2-methoxybenzene sulfonamide. The invention adopts the compound with the structure shown in the formula 2 as a reaction raw material, and constructs a chiral center through one-step reaction with the format product with the structure shown in the formula 1, thereby improving the atom utilization rate; then chlorosulfonic acid is used as a raw material to carry out chlorosulfonation and ammonification reaction by a one-step method; and finally, carrying out reduction deprotection on the obtained product to obtain (R) -5- (2-aminopropyl) -2-methoxyl benzenesulfonamide. The preparation method provided by the invention simplifies the operation flow, has less three wastes, has high yield in each step, and the obtained (R) -5- (2-aminopropyl) -2-methoxyl benzenesulfonamide product has high purity and is suitable for industrial production.
Drawings
FIG. 1 is a flow chart of the preparation of (R) -5- (2-aminopropyl) -2-methoxybenzenesulfonamide provided in the examples of the present invention;
FIG. 2 is a schematic diagram of a format reaction in an embodiment of the invention;
FIG. 3 is a nuclear magnetic pattern of the (R) -5- (2-aminopropyl) -2-methoxybenzenesulfonamide product prepared in accordance with the present invention;
FIG. 4 is a HPLC detection chart of the (R) -5- (2-aminopropyl) -2-methoxybenzenesulfonamide product prepared in accordance with the present invention;
FIG. 5 is a graph showing the chiral purity of the (R) -5- (2-aminopropyl) -2-methoxybenzenesulfonamide product prepared according to the present invention.
Detailed Description
The invention provides a preparation method of (R) -5- (2-aminopropyl) -2-methoxyl benzenesulfonamide, which comprises the following steps:
(1) Mixing p-bromoanisole, magnesium metal, an initiator and an organic solvent to perform a first-stage format reaction to obtain a first-stage format reaction solution; the first-stage format reaction liquid contains a format product with a structure shown in a formula 1; mixing the first-stage format reaction liquid with a compound with a structure shown in a formula 2 to perform a second-stage format reaction to obtain a compound with a structure shown in a formula 3;
(2) Mixing chlorosulfonic acid with a compound with a structure shown in a formula 3 for chlorosulfonation reaction, and mixing the obtained chlorosulfonation reaction solution with ammonia water for ammoniation reaction to obtain a compound with a structure shown in a formula 4;
(3) In the atmosphere of hydrogen, the compound with the structure shown in the formula 4, an organic solvent and a palladium catalyst are mixed for reduction reaction to obtain (R) -5- (2-aminopropyl) -2-methoxybenzene sulfonamide.
In the present invention, all preparation materials/components are commercially available products well known to those skilled in the art unless specified otherwise.
Mixing p-bromoanisole, magnesium metal, an initiator and an organic solvent to perform a first-stage format reaction to obtain a first-stage format reaction solution; the first-stage format reaction liquid contains a format product with a structure shown in a formula 1; mixing the first-stage format reaction liquid with a compound with a structure shown in a formula 2 to perform a second-stage format reaction to obtain a compound with a structure shown in a formula 3;
in the present invention, the initiator is preferably 1, 2-dibromoethane and iodine. The first organic solvent preferably includes one or more of tetrahydrofuran, methyltetrahydrofuran, and diethyl ether. The mass ratio of the p-bromoanisole to the metal magnesium is preferably 1:0.1 to 0.2, more preferably 1:0.12 to 0.17. The mass ratio of the p-bromoanisole to the initiator is preferably 1:0.004 to 0.005, more preferably 1:0.0048. the mass ratio of the 1, 2-dibromoethane to the iodine is preferably 1:0.2-0.3, and more preferably 1:0.2. The mass ratio of the p-bromoanisole to the compound with the structure shown in the formula 2 is preferably 1:1 to 2, more preferably 1:1.2 to 1.5, most preferably 1:1.328. The invention has no special requirement on the dosage of the first organic solvent, and ensures that the reaction is carried out smoothly.
In the present invention, the first stage format reaction preferably includes the steps of: in the atmosphere of protective gas, mixing part of the first organic solvent, part of the p-bromoanisole, metal magnesium and an initiator for pre-reaction to obtain a pre-reaction liquid; mixing the pre-reaction liquid, the residual para-bromoanisole and the residual first organic solvent, and continuing to react under the condition of reflux to obtain a format reaction liquid. In the present invention, the shielding gas is preferably nitrogen. The volume ratio of the first organic solvent to the remaining first organic solvent is preferably 1:1. The mass ratio of part of the para-bromoanisole to the rest of the para-bromoanisole is 1:24. the temperature of the pre-reaction is preferably 30-35 ℃, more preferably 35 ℃; the holding time is preferably 30 to 60 minutes, more preferably 30 minutes. In the present invention, the mixing of the pre-reaction liquid, the remaining para-bromoanisole and the remaining first organic solvent is preferably: dissolving the residual para-bromoanisole in the residual first organic solvent to obtain residual para-bromoanisole solution; the remaining para-bromoanisole solution was added dropwise to the pre-reaction solution. The continued reaction is carried out under stirring, preferably for a period of 4 hours.
After the first-stage format reaction liquid is obtained, the method preferably reduces the temperature of the first-stage format reaction liquid to 0-5 ℃, and then mixes the first-stage format reaction liquid with the compound with the structure shown in the formula 2 to carry out the second-stage format reaction to obtain the compound with the structure shown in the formula 3. FIG. 2 is a schematic of the mechanism of the grignard reaction of the present invention, wherein the intermediate obtained in the second stage grignard reaction does not need to be isolated. In the present invention, the compound of the structure represented by formula 2 is preferably used in the form of an organic solution of the compound of the structure represented by formula 2, and the organic solvent in the organic solution of the compound of the structure represented by formula 2 is a first organic solvent. When the cooled first-stage format reaction liquid is mixed with the compound of the structure shown in the formula 2, the organic solution of the compound of the structure shown in the formula 2 is preferably added dropwise into the first-stage format reaction liquid. The temperature of the second stage format reaction is preferably 0 to 70 ℃, more preferably 20 to 50 ℃, more preferably 25 to 35 ℃, and even more preferably 25 to 30 ℃; the time is preferably 1 to 2 days, more preferably 2 days. The second stage format reaction is carried out under stirring.
In the invention, after the second-stage format reaction is finished, a second-stage format reaction liquid is obtained, wherein the second-stage format reaction liquid contains a first intermediate; the chemical structural formula of the first intermediate is as follows:
after the second-stage format reaction is finished, the obtained second-stage format reaction liquid is preferably dripped into hydrochloric acid to be stirred and mixed, and the liquid is separated to obtain an organic phase and a water phase; and extracting the aqueous phase with a first organic solvent, and combining the obtained extracted organic phase with an organic phase obtained by liquid separation to obtain an organic phase product. In the invention, the organic phase product contains a second intermediate, and the chemical structural formula of the second intermediate is as follows:
sequentially performing first drying and first solid-liquid separation on the organic phase product, and concentrating the obtained liquid product to dryness to obtain a first solid product; mixing the first solid product and trifluoroacetic acid (TFA), cooling to 0-5 ℃, preferably 5 ℃, dropwise adding triethylsilane into the mixture, heating to 15-35 ℃, preferably 25 ℃, reacting, and concentrating the obtained reaction solution under reduced pressure until the reaction solution is dried to obtain a second solid product; and stirring and mixing the second solid product and cyclohexane, and then carrying out second solid-liquid separation, and drying the obtained solid product to obtain the compound with the structure shown in the formula 3. The mass content of the hydrochloric acid is preferably 10%, and the ratio of the mass of the p-bromoanisole to the volume of the hydrochloric acid is preferably 2.5kg:20L, and the stirring and mixing time is preferably 1-3 h. The reagent used in the first drying is preferably anhydrous sodium sulfate. The first solid-liquid separation is preferably filtration. The mass ratio of the p-bromoanisole to the trifluoroacetic acid is preferably 1:4-5.5, more preferably 1:4.5-5, and most preferably 1:4.8. The mass ratio of the bromoanisole to the triethylsilane is preferably 1:1-2.5, more preferably 1:1.2-2, and most preferably 1:1.4. The reaction time is preferably 1 to 3 hours, more preferably 2 hours. The temperature of the stirring and mixing is room temperature and the time is 2h. The second solid-liquid separation is preferably suction filtration.
After the compound with the structure shown in the formula 3 is obtained, chlorosulfonic acid and the compound with the structure shown in the formula 3 are mixed for chlorosulfonation reaction, and the obtained chlorosulfonation reaction liquid and ammonia water are mixed for ammoniation reaction to obtain the compound with the structure shown in the formula 4.
In the present invention, the mass ratio of the compound of the structure represented by formula 3 to chlorosulfonic acid is preferably 1:5 to 15, more preferably 1:6 to 12, more preferably 1:10. when the chlorosulfonic acid is mixed with the compound with the structure shown in the formula 3: the compound of the structure shown in formula 3 is preferably mixed in batches, the mixing temperature is preferably less than or equal to 15 ℃, the mixing is carried out under stirring, and the stirring time is 5min. The chlorosulfonation reaction is preferably carried out at a temperature of 0 to 80 ℃, more preferably 30 to 70 ℃, still more preferably 40 to 60 ℃; the time is preferably 1 to 2 hours, more preferably 1 hour. In the present invention, the chlorosulfonation reaction liquid obtained by the chlorosulfonation reaction is preferably subjected to a post-treatment and then mixed with ammonia, and in the present invention, the post-treatment preferably comprises: the chlorosulfonation reaction liquid is added into crushed ice in a dropwise manner, and then the pH value is adjusted to 7-8 by a pH regulator. The pH regulator is preferably first ammonia water, and the concentration of the first ammonia water used for regulating the pH value is not particularly required in the invention.
In the present invention, the mass concentration of the aqueous ammonia is preferably 25 to 28wt%. The ammonia water is industrial ammonia water. The mass ratio of the compound of the structure represented by formula 3 to aqueous ammonia is preferably 1:4. The temperature of the ammonification reaction is preferably 0 to 80 ℃, more preferably 20 to 50 ℃, and even more preferably 25 to 40 ℃; the time is preferably 1 to 2 hours, more preferably 1 hour.
In the invention, an ammoniation reaction liquid is obtained after the ammoniation reaction, and the invention also comprises the steps of carrying out heat preservation crystallization after cooling the ammoniation reaction liquid, and obtaining a compound with a structure shown in a formula 4 after solid-liquid separation; the temperature of the heat preservation crystallization is preferably 0-30 ℃, more preferably 0-5 ℃; the time is preferably 1 to 24 hours, more preferably 12 hours. The heat preservation crystallization is carried out under the condition of stirring. After the heat preservation crystallization is finished, the obtained crystallization solution is preferably subjected to solid-liquid separation, and the obtained solid product is dried to obtain the compound with the structure shown in the formula 4. The solid-liquid separation is preferably suction filtration.
After obtaining the compound of the structure shown in formula 4, the present invention mixes the compound of the structure shown in formula 4, an organic solvent (hereinafter referred to as a second organic solvent) and a palladium catalyst in an atmosphere of hydrogen gas to perform a reduction reaction, thereby obtaining (R) -5- (2-aminopropyl) -2-methoxybenzenesulfonamide.
In the present invention, the second organic solvent is preferably one or more of methanol, ethanol, isopropanol and n-butanol, more preferably ethanol. The palladium catalyst is preferably palladium carbon, and the mass content of palladium in the palladium carbon is preferably 5 to 10%, more preferably 5%. The mass ratio of the compound of the structure shown in formula 4 to the palladium catalyst is preferably 1:0.01 to 0.5, more preferably 1:0.02 to 0.1. The invention has no special requirement on the dosage of the second organic solvent, and ensures that the reaction is carried out smoothly.
In the present invention, the pressure of the hydrogen gas is preferably 0.01 to 2MPa, more preferably 0.1 to 0.5MPa. The temperature of the reduction reaction is preferably room temperature, and the time is preferably 2 to 3 hours, more preferably 2.5 hours.
After the reduction reaction, the liquid-solid separation of the obtained reduction reaction is preferable, and the obtained liquid product is inspected and concentrated to be dry to obtain the (R) -5- (2-aminopropyl) -2-methoxybenzene sulfonamide. In the present invention, the solid-liquid separation is preferably filtration.
The technical solutions provided by the present invention are described in detail below in conjunction with examples for further illustrating the present invention, but they should not be construed as limiting the scope of the present invention.
The following example is carried out according to the preparation scheme of FIG. 1, in which SM-1 is para-bromoanisole; SM-2 is a compound of a structure shown in formula 2, the chemical name is (S) -4-methyl-5-oxo oxazolidine-3-carboxylic acid benzyl ester, TX-1 is a compound of a structure shown in formula 1, the chemical name is (4-methoxyphenyl) magnesium bromide, TX-2 is a compound of a structure shown in formula 3, the chemical name is (R) - (1- (4-methoxyphenyl) propan-2-yl) carbamic acid benzyl ester, TX-3 is a compound of a structure shown in formula 4, the chemical name is (R) - (1- (4-methoxy-3-sulfamylphenyl) propan-2-yl) carbamic acid benzyl ester, and TX-4 is (R) -5- (2-aminopropyl) -2-methoxybenzenesulfonamide.
Example 1
Adding 10L of tetrahydrofuran and 100g of p-bromoanisole under the protection of nitrogen, adding 10g of magnesium 387g, 10g of 1, 2-dibromoethane and 2g of iodine into a 50L reaction kettle, heating to 35 ℃, preserving heat for 30 minutes, enabling the color to disappear, dropwise adding 2.4kg of 10L of tetrahydrofuran solution of the p-bromoanisole, after the addition, refluxing and stirring for 4 hours, reducing the temperature to 0 ℃, dropwise adding 3.32kg of 10L of tetrahydrofuran solution of (S) -4-methyl-5-oxo-oxazolidine-3-carboxylic acid benzyl ester, heating to 28 ℃ after the addition, stirring and reacting for 2 days, dripping the reaction liquid into 20L of 10% hydrochloric acid, preserving heat and stirring for 3 hours, separating the liquid, extracting the water layer by 10L of tetrahydrofuran once, merging the water layer into an organic layer, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until the filtrate is dry, adding 12kg of TFA, reducing the temperature to 5 ℃ and dropwise adding 3.5kg of triethylsilane, after the addition, heating to 25 ℃ for 2 hours, concentrating the filtrate under reduced pressure until the filtrate is dry, adding 10L of cyclohexane, stirring for 2 hours at room temperature, stirring for 2 hours, dropwise adding 20L of hydrochloric acid, dropwise adding 20L of 10% hydrochloric acid, drying, and filtering to obtain a solid, and obtaining a white product, of which is similar to the dry product, and has a yield of 23.54%.
30kg of chlorosulfonic acid is added into a 50L reaction kettle, 3kg of TX-2 is added in batches, the temperature is controlled to be 15 ℃, stirring is carried out for 5 minutes after the addition, the temperature is raised to be 50 ℃ for reaction for 1 hour, the temperature is reduced to 25 ℃, the mixture is dripped into 75kg of crushed ice, the pH is regulated to 7-8 after the addition, 12kg of industrial ammonia water (the mass content of the industrial ammonia water is 25 wt%) is added, the reaction is carried out for 1 hour at 25 ℃, the temperature is reduced to 0-5 ℃, the temperature is kept for 12 hours, the stirring is carried out, suction filtration is carried out, and the obtained solid product is dried, thus obtaining off-white solid TX-33.5kg, and the yield is 92.3%.
In a 5L high-pressure reaction kettle, 3L of ethanol, 3kg of TX-3, 60g of 5% palladium carbon and hydrogen under the pressure of 0.2Mpa are added, the reaction is carried out for 2.5 hours at room temperature, filtration is carried out, and the filtrate is concentrated to dryness under reduced pressure to obtain white solid TX-41.84kg, and the yield is 94.8%.
The nuclear magnetic pattern of the product TX-4 prepared in this example is shown in FIG. 3, and the nuclear magnetic data are as follows: 1 H-NMR(500MHz,DMSO-d6)δ:7.55(1H,d),7.38(1H,m),7.12(1H,d),3.87(3H,s),2.97(1H,m),2.55(2H,m),0.94(3H,d).
the HPLC detection pattern of the product TX-4 prepared in this example is shown in FIG. 4. As can be seen from FIG. 4, the purity of the (R) -5- (2-aminopropyl) -2-methoxybenzenesulfonamide product prepared in this example was 99.881%.
The chiral purity of the product TX-4 prepared in this example is shown in FIG. 5. As can be seen from FIG. 5, the chiral purity of the product prepared in this example was 100%.
As can be seen from example 1, the invention adopts the amino acid derivative one-step method to construct chiral centers, thereby improving the atom utilization rate; the chlorosulfonation and ammonification reaction are carried out by adopting a one-step method, three wastes are reduced, the reaction yield is improved, and the obtained key intermediate TX-4 has high purity and is suitable for industrial production.
Although the foregoing embodiments have been described in some, but not all embodiments of the invention, other embodiments may be obtained according to the present embodiments without departing from the scope of the invention.
Claims (10)
1. A method for preparing (R) -5- (2-aminopropyl) -2-methoxybenzene sulfonamide, which is characterized by comprising the following steps:
(1) Mixing p-bromoanisole, magnesium metal, an initiator and an organic solvent to perform a first-stage format reaction to obtain a first-stage format reaction solution; the first-stage format reaction liquid contains a format product with a structure shown in a formula 1; mixing the first-stage format reaction liquid with a compound with a structure shown in a formula 2 to perform a second-stage format reaction to obtain a compound with a structure shown in a formula 3;
(2) Mixing chlorosulfonic acid with a compound with a structure shown in a formula 3 for chlorosulfonation reaction, and mixing the obtained chlorosulfonation reaction solution with ammonia water for ammoniation reaction to obtain a compound with a structure shown in a formula 4;
(3) In the atmosphere of hydrogen, the compound with the structure shown in the formula 4, an organic solvent and a palladium catalyst are mixed for reduction reaction to obtain (R) -5- (2-aminopropyl) -2-methoxybenzene sulfonamide.
2. The preparation method according to claim 1, wherein the mass ratio of the p-bromoanisole to the magnesium metal is 1:0.1 to 0.2; the mass ratio of the p-bromoanisole to the compound with the structure shown in the formula 2 is 1:1 to 2.
3. The method of claim 1, wherein the initiator is 1, 2-dibromoethane and iodine; the mass ratio of the 1, 2-dibromoethane to the iodine is 1:0.2-0.3; the mass ratio of the p-bromoanisole to the initiator is 1: 0.004-0.005.
4. A method according to any one of claims 1 to 3, wherein in step (1), the first stage format reaction comprises the steps of: in the atmosphere of protective gas, mixing part of organic solvent, part of p-bromoanisole, metal magnesium and initiator for pre-reaction to obtain pre-reaction liquid; mixing the pre-reaction liquid, the residual para-bromoanisole and the residual organic solvent, and continuing to react under the condition of reflux to obtain a format reaction liquid; the mass ratio of part of the para-bromoanisole to the rest of the para-bromoanisole is 1:24, a step of detecting the position of the base; the temperature of the pre-reaction is 30-35 ℃, and the heat preservation time is 30-60 min.
5. The method according to claim 1, wherein in the step (1), a second-stage format reaction solution is obtained after the second-stage format reaction, and the second-stage format reaction solution contains a first intermediate; the chemical structural formula of the first intermediate is as follows:
mixing the second-stage format reaction solution with hydrochloric acid, and separating the solution to obtain an organic phase and a water phase; extracting the aqueous phase with a first organic solvent, and combining the obtained extracted organic phase with an organic phase obtained by liquid separation to obtain an organic phase product, wherein the organic phase product contains a second intermediate, and the chemical structural formula of the second intermediate is as follows:
and mixing the organic phase product, trifluoroacetic acid and triethylsilane for reaction to obtain the compound with the structure shown in the formula 3.
6. The method according to claim 1 or 5, wherein the second stage format reaction is carried out at a temperature of 0 to 70 ℃ for a period of 1 to 2 days.
7. The preparation method according to claim 1, wherein the mass ratio of the compound of the structure represented by formula 3 to chlorosulfonic acid is 1:5 to 15; the temperature of chlorosulfonation reaction and ammonification reaction is independently 0-80 ℃.
8. The preparation method of the compound as claimed in claim 1 or 7, wherein the ammoniation reaction liquid is obtained after the ammoniation reaction, and the preparation method further comprises the steps of cooling the ammoniation reaction liquid, performing heat preservation crystallization, and performing solid-liquid separation to obtain the compound with the structure shown in the formula 4; the temperature of the heat preservation crystallization is 0-30 ℃ and the time is 1-24 h.
9. The preparation method according to claim 1, wherein the palladium catalyst is palladium-carbon, and the mass content of palladium in the palladium-carbon is 5-10%;
the mass ratio of the compound with the structure shown in the formula 4 to the palladium catalyst is 1:0.01 to 0.5.
10. The production method according to claim 1 or 9, wherein the pressure of the hydrogen gas is 0.01 to 2MPa.
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