CN110981828A - Method for synthesizing dimethyl cysteamine hydrochloride - Google Patents
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- CN110981828A CN110981828A CN201911184710.3A CN201911184710A CN110981828A CN 110981828 A CN110981828 A CN 110981828A CN 201911184710 A CN201911184710 A CN 201911184710A CN 110981828 A CN110981828 A CN 110981828A
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- hydrochloric acid
- isopropylthiazolidine
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- 238000000034 method Methods 0.000 title claims abstract description 25
- MBPAUMHSIFBANF-UHFFFAOYSA-N 1-amino-2-methylpropane-2-thiol Chemical compound CC(C)(S)CN MBPAUMHSIFBANF-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 41
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- UEHKBJZDQOQOLX-UHFFFAOYSA-N 5,5-dimethyl-2-propan-2-yl-1,3-thiazolidine Chemical compound CC(C)C1NCC(C)(C)S1 UEHKBJZDQOQOLX-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 15
- -1 5, 5-dimethyl-2-substituted thiazolidine Chemical class 0.000 claims abstract description 11
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229940067157 phenylhydrazine Drugs 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 9
- 239000012452 mother liquor Substances 0.000 claims abstract description 7
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 8
- 239000012071 phase Substances 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000010413 mother solution Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 238000012840 feeding operation Methods 0.000 abstract description 2
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- HHQSUSGDCHSDTO-UHFFFAOYSA-N 5,5-dimethyl-2-propan-2-yl-4h-1,3-thiazole Chemical compound CC(C)C1=NCC(C)(C)S1 HHQSUSGDCHSDTO-UHFFFAOYSA-N 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- MFBPRQKHDIVLOJ-AFFLPQGKSA-N 133868-46-9 Chemical compound Cl.CC(C)[C@@H](N)C(=O)NCC(C)(C)SCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 MFBPRQKHDIVLOJ-AFFLPQGKSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 231100000086 high toxicity Toxicity 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000009434 installation Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 150000004141 diterpene derivatives Chemical class 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical compound C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- UURAUHCOJAIIRQ-QGLSALSOSA-N tiamulin Chemical compound CCN(CC)CCSCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 UURAUHCOJAIIRQ-QGLSALSOSA-N 0.000 description 1
- 229960004885 tiamulin Drugs 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 239000002351 wastewater Substances 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
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for synthesizing dimethyl cysteamine hydrochloride, which comprises the steps of carrying out ring-opening and ring-closing reaction on 5, 5-dimethyl-2-isopropyl thiazolidine under the action of hydrochloric acid, a solvent, phenylhydrazine and aldehyde to obtain 5, 5-dimethyl-2-substituted thiazolidine mother liquor; hydrochloric acid is directly added into the 5, 5-dimethyl-2-substituted thiazolidine mother liquor, and the dimethyl cysteamine hydrochloride is obtained through ring opening reaction. The invention discloses a one-pot preparation process, which reduces reaction steps, and does not reduce the purity by controlling the material proportion and the feeding operation details.
Description
Technical Field
The invention relates to a method for synthesizing dimethyl cysteamine hydrochloride.
Background
The dimethyl cysteamine hydrochloride is an important intermediate of valnemulin hydrochloride, and the valnemulin hydrochloride is a new generation of pleuromutilin semi-synthetic antibiotic, belongs to diterpene, belongs to the same class of medicines as the tiamulin, and is an antibiotic special for animals. The composition is mainly used for preventing and treating mycoplasma diseases and gram-positive bacteria infection of pigs, cattle, sheep and poultry, and has the characteristics of wide antibacterial spectrum, strong antibacterial activity, excellent pharmacokinetic characteristics, low residue, high safety and the like.
The preparation method is reported in the literature at present, and the preparation method comprises the following specific steps:
patent CN102432510A discloses a method for synthesizing dimethyl cysteamine hydrochloride:
(I) ring closing reaction: synthesizing 5, 5-dimethyl-2-isopropyl thiazoline by taking isobutyraldehyde, elemental sulfur, ammonia gas and triethylamine as raw materials;
(II) reduction reaction: reducing 5, 5-dimethyl-2-isopropyl thiazoline into 5, 5-dimethyl-2-isopropyl thiazolidine by using sodium borohydride aqueous solution and acid;
(III) ring-opening reaction: 5, 5-dimethyl-2-isopropyl thiazolidine and phenylhydrazine are reacted to obtain dimethyl cysteamine hydrochloride.
The invention has the advantages of easily obtained reaction raw materials and relatively mild reaction conditions, but still has the following defects: 1. the first step of reaction is carried out in a pressure-resistant reaction kettle by using ammonia gas, the ammonia gas is flammable and explosive, has high toxicity, increases the complexity and safety risk of the process to a certain extent, and has strict safety requirements on process equipment and installation thereof; 2. during the second-step reduction reaction, sodium borohydride solution and acid are required to be added dropwise at the same time, so that the operation is inconvenient; 3. the ring-opening reaction uses phenylhydrazine with carcinogenicity as a reaction reagent, trace residual phenylhydrazine is carried in a final product, the residue of the high-toxicity and strong teratogenicity substance in the product can seriously affect the use safety of the veterinary drug valnemulin hydrochloride, and huge potential safety hazards of drug use exist.
Patent CN105367467A discloses a method for synthesizing dimethyl cysteamine hydrochloride:
(I) ring closing reaction: synthesizing 5, 5-dimethyl-2-isopropyl thiazoline by taking isobutyraldehyde, elemental sulfur, ammonia gas and triethylamine as raw materials;
(II) reduction reaction: reducing 5, 5-dimethyl-2-isopropyl thiazoline into 5, 5-dimethyl-2-isopropyl thiazolidine by using sodium borohydride aqueous solution and acid;
(III) ring-opening reaction: reacting the 5, 5-dimethyl-2-isopropyl thiazolidine with a hydrochloric acid solution under the protection of nitrogen to obtain dimethyl cysteamine hydrochloride.
The reaction of the invention is similar to CN102432510A, and the process disadvantages are as follows: 1. the first step of reaction is carried out in a pressure-resistant reaction kettle by using ammonia gas, the ammonia gas is flammable and explosive, has high toxicity, increases the complexity and safety risk of the process to a certain extent, and has strict safety requirements on process equipment and installation thereof; 2. during the second-step reduction reaction, sodium borohydride solution and acid are required to be added dropwise at the same time, so that the operation is inconvenient; after the reaction, the acid aqueous solution of the product is directly used for the next reaction, so that the inorganic salt and part of impurities in the final product are increased, and the process repeatability is poor; 3. the process adopts steam distillation for ring opening in the third step of ring opening reaction, but the ring opening reaction speed catalyzed by hydrochloric acid is very slow, the proper conversion rate can be achieved only by continuously distilling for dozens to hundreds of hours at the reflux temperature, the time is greatly increased along with the amplification of the synthesis scale, the volatilization loss of products in the distillation process is large, and high COD irritative wastewater containing isobutyraldehyde with the weight of a substrate more than 100 times that of the isobutyraldehyde is generated, so that the process has the disadvantages of overhigh energy consumption, low yield, great limitation on the productivity and unsuitability for large-scale production.
Furthermore, it is reported in J.org.chem.1994,59, 7019-7026; the isobutyraldehyde is used as a raw material to react with disulfide dichloride to obtain 2,2 '-dialdehyde diisobutyldithium ether, the 2, 2' -dialdehyde diisobutyldithium ether and methoxylamine hydrochloride are reacted to form oxime, and finally, the oxime is reduced to dimethyl cysteamine hydrochloride by lithium aluminum hydride. The process route has harsh chlorination and reduction reaction conditions, and the reagent has high price and is not suitable for industrial production.
In addition, patent CN106565563A discloses a series of routes, but these routes are all carried out in a plurality of reaction vessels, which is clearly warned by those skilled in the art that it is not desirable to carry out the reaction continuously.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the prejudice of the prior art and provide a one-pot preparation process, which reduces reaction steps and does not reduce the purity by controlling the material proportion.
The invention relates to a method for synthesizing dimethyl cysteamine hydrochloride, which comprises the steps of carrying out ring opening and ring closing reactions on 5, 5-dimethyl-2-isopropyl thiazolidine under the action of hydrochloric acid, a solvent, phenylhydrazine and aldehyde to obtain 5, 5-dimethyl-2-substituted thiazolidine mother liquor; hydrochloric acid is directly added into the 5, 5-dimethyl-2-substituted thiazolidine mother liquor, and the dimethyl cysteamine hydrochloride is obtained through ring opening reaction.
Alternatively, the order of addition is 5, 5-dimethyl-2-isopropylthiazolidine is added to hydrochloric acid first, followed by the solvent and phenylhydrazine.
Optionally, the solvent is toluene.
Alternatively, the aldehyde in the reaction is a 2-aldehyde pyridine.
Optionally, the molar ratio of the 5, 5-dimethyl-2-isopropylthiazolidine to the phenylhydrazine is 0.7-1.5, the weight ratio of the 5, 5-dimethyl-2-isopropylthiazolidine to the solvent is 0.1-1.0, the molar ratio of the 5, 5-dimethyl-2-isopropylthiazolidine to the aldehyde is 1.0-10.0, the molar ratio of the 5, 5-dimethyl-2-isopropylthiazolidine to the hydrochloric acid used for the ring-opening and ring-closing reaction is 1.5-2: 1, and the molar ratio of the 5, 5-dimethyl-2-isopropylthiazolidine to the hydrochloric acid used for the ring-opening and ring-closing reaction.
Alternatively, the molar ratio of 5, 5-dimethyl-2-isopropylthiazolidine to hydrochloric acid used for the ring-opening reclosure reaction is 2:1 and the molar ratio to hydrochloric acid used for the ring-opening reaction is 1: 10.
Optionally, the ring opening reclosing reaction comprises: heating to reflux reaction, after the reaction is finished, separating an organic phase, extracting a water phase twice by using a solvent, adding aldehyde into the water phase to adjust the pH value to 6.0-12.0, extracting by using the solvent, combining the organic phases for desolventizing, and distilling under reduced pressure to obtain the 5, 5-dimethyl-2-substituted thiazolidine. The solvent used for the extraction is preferably toluene.
Optionally, the ring-opening reaction comprises reacting at 50-120 ℃, distilling out low-boiling-point substances at normal pressure during the reaction, dehydrating, and crystallizing to obtain the dimethyl cysteamine hydrochloride.
The preparation of 5, 5-dimethyl-2-isopropylthiazolidine can be prepared by the prior art.
The invention has the beneficial effects that:
the invention discloses a one-pot preparation process, which reduces reaction steps, and does not reduce the purity by controlling the material proportion and the feeding operation details.
Detailed Description
Example 1
720g of sulfur powder, 3250g of isobutyraldehyde and 100g of triethylamine are added into a 10L glass reaction kettle, heated to 55 ℃ and slightly refluxed, 1665g of ammonia water is added dropwise, the temperature is raised to 90 ℃ after dropwise addition, and the temperature is kept for reaction for 2 hours. Cooling to room temperature, standing for layering, removing a water layer, and washing an organic phase once, wherein the organic phase is the 5, 5-dimethyl-2-isopropyl thiazoline.
Example 2
5, 5-dimethyl-2-isopropylthiazoline (1350g) prepared in example 1 and 6N HCl (3000g) were put into a 10L glass reaction vessel, cooled to 15 ℃ and an aqueous solution of sodium borohydride (165 g of sodium borohydride was prepared by dissolving in 2000g of water) was added dropwise. After dripping, toluene is added for extraction twice, and the pH value of the aqueous phase is adjusted to 5.8. Standing for layering, extracting the water phase once with toluene, combining the organic phases for desolventizing, and distilling under reduced pressure to obtain colorless transparent liquid 5, 5-dimethyl-2-isopropylthiazolidine.
Example 3
5, 5-dimethyl-2-isopropylthiazolidine (79.5g) prepared in example 2 is added into 0.5 molar equivalent hydrochloric acid, then toluene (280g) and phenylhydrazine (48.6g) are added into the mixture, the mixture is added into a glass reaction kettle for a time, the mixture is heated to reflux, and the reaction is kept for 2 hours. Cooling to room temperature, taking a water phase by liquid separation, extracting with toluene once, adding 2-aldehyde pyridine (80.3g) into the water phase, adjusting the pH to 10 with liquid alkali, stirring for 2 hours at room temperature, extracting with toluene twice, combining organic phases, washing with water, desolventizing, and distilling under reduced pressure to obtain 5, 5-dimethyl-2- (2-pyridyl) thiazolidine mother liquor.
Directly adding 10 molar equivalent of concentrated hydrochloric acid into the 5, 5-dimethyl-2- (2-pyridyl) thiazolidine mother liquor, heating to 115 ℃ for reacting for 40 hours, distilling out low-boiling-point substances at normal pressure during the reaction, dehydrating after the reaction, and crystallizing a crude product to obtain 31.6g of dimethyl cysteamine hydrochloride, wherein the content of the dimethyl cysteamine hydrochloride is up to 98.0 percent by detection.
Claims (9)
1. A method for synthesizing dimethyl cysteamine hydrochloride is characterized in that: 5, 5-dimethyl-2-isopropyl thiazolidine is subjected to ring opening and ring closing reaction under the action of hydrochloric acid, a solvent, phenylhydrazine and aldehyde to obtain a 5, 5-dimethyl-2-substituted thiazolidine mother solution; hydrochloric acid is directly added into the 5, 5-dimethyl-2-substituted thiazolidine mother liquor, and the dimethyl cysteamine hydrochloride is obtained through ring opening reaction.
2. The method of claim 1, further comprising: the feeding sequence is that 5, 5-dimethyl-2-isopropyl thiazolidine is firstly added into hydrochloric acid, and then solvent and phenylhydrazine are added.
3. A method according to claim 1 or 2, characterized by: the solvent is toluene.
4. A method according to claim 1 or 2, characterized by: in the reaction, aldehyde is 2-aldehyde pyridine.
5. The method of claim 4, wherein: the molar ratio of the 5, 5-dimethyl-2-isopropylthiazolidine to the phenylhydrazine is 0.7-1.5, the weight ratio of the 5, 5-dimethyl-2-isopropylthiazolidine to the solvent is 0.1-1.0, the molar ratio of the 5, 5-dimethyl-2-isopropylthiazolidine to the aldehyde is 1.0-10.0, the molar ratio of the 5, 5-dimethyl-2-isopropylthiazolidine to hydrochloric acid used for the ring opening and ring closing reaction is 1.5-2: 1, and the molar ratio of the 5, 5-dimethyl-2-isopropylthiazolidine to hydrochloric acid used for the ring opening and ring closing reaction is 1: 10-15.
6. The method of claim 5, wherein: the molar ratio of the 5, 5-dimethyl-2-isopropylthiazolidine to the hydrochloric acid used for the ring-opening and reclosing reaction is 2:1, and the molar ratio of the 5, 5-dimethyl-2-isopropylthiazolidine to the hydrochloric acid used for the ring-opening and reclosing reaction is 1: 10.
7. The method of claim 6, wherein the ring opening reclosing reaction comprises: heating to reflux reaction, after the reaction is finished, separating an organic phase, extracting a water phase twice by using a solvent, adding aldehyde into the water phase to adjust the pH value to 6.0-12.0, extracting by using the solvent, combining the organic phases for desolventizing, and distilling under reduced pressure to obtain the 5, 5-dimethyl-2-substituted thiazolidine.
8. The method of claim 7, wherein: the solvent used for the extraction was toluene.
9. The method of claim 1, further comprising: the ring-opening reaction comprises the steps of reacting at 50-120 ℃, distilling out low-boiling-point substances at normal pressure during the reaction, dehydrating, and crystallizing to obtain the dimethyl cysteamine hydrochloride.
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| CN201911184710.3A CN110981828A (en) | 2019-11-27 | 2019-11-27 | Method for synthesizing dimethyl cysteamine hydrochloride |
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| CN201911184710.3A CN110981828A (en) | 2019-11-27 | 2019-11-27 | Method for synthesizing dimethyl cysteamine hydrochloride |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101941929A (en) * | 2009-07-08 | 2011-01-12 | 赵云现 | Method for preparing 2,2-dimethyl cysteamine salts |
| CN105367467A (en) * | 2015-12-01 | 2016-03-02 | 苏利制药科技江阴有限公司 | Synthetic method of dimethyl cysteamine hydrochloride |
| CN106008292A (en) * | 2016-06-17 | 2016-10-12 | 杭州扬帆化工科技有限公司 | Method for synthesizing 2,2-dimethyl cysteamine hydrochloride |
| CN106565563A (en) * | 2016-11-10 | 2017-04-19 | 杭州扬帆化工科技有限公司 | Dimethyl cysteamine hydrochloride synthetic process |
-
2019
- 2019-11-27 CN CN201911184710.3A patent/CN110981828A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101941929A (en) * | 2009-07-08 | 2011-01-12 | 赵云现 | Method for preparing 2,2-dimethyl cysteamine salts |
| CN105367467A (en) * | 2015-12-01 | 2016-03-02 | 苏利制药科技江阴有限公司 | Synthetic method of dimethyl cysteamine hydrochloride |
| CN106008292A (en) * | 2016-06-17 | 2016-10-12 | 杭州扬帆化工科技有限公司 | Method for synthesizing 2,2-dimethyl cysteamine hydrochloride |
| CN106565563A (en) * | 2016-11-10 | 2017-04-19 | 杭州扬帆化工科技有限公司 | Dimethyl cysteamine hydrochloride synthetic process |
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Application publication date: 20200410 |