CN112645995A - Synthetic method of 3N-isepamicin - Google Patents

Synthetic method of 3N-isepamicin Download PDF

Info

Publication number
CN112645995A
CN112645995A CN202011583251.9A CN202011583251A CN112645995A CN 112645995 A CN112645995 A CN 112645995A CN 202011583251 A CN202011583251 A CN 202011583251A CN 112645995 A CN112645995 A CN 112645995A
Authority
CN
China
Prior art keywords
isepamicin
follows
steps
synthesizing
water
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202011583251.9A
Other languages
Chinese (zh)
Inventor
王涛
王彬彬
王庆林
李晓明
曹娜
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhuohe Pharmaceutical Group Co ltd
Original Assignee
Zhuohe Pharmaceutical Group Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhuohe Pharmaceutical Group Co ltd filed Critical Zhuohe Pharmaceutical Group Co ltd
Priority to CN202011583251.9A priority Critical patent/CN112645995A/en
Publication of CN112645995A publication Critical patent/CN112645995A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
    • C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
    • C07H15/236—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2 a saccharide radical being substituted by an alkylamino radical in position 3 and by two substituents different from hydrogen in position 4, e.g. gentamicin complex, sisomicin, verdamycin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a synthetic method of 3N-isepamicin, which comprises the following steps: step 1): protecting the B-terminal chain amino group of the gentamicin to obtain an intermediate 1; step 2): performing silanization protection on the intermediate 1 to obtain an intermediate 2; step 3): protecting the amino group of the intermediate 2 to obtain an intermediate 3; step 4): desilication protection of the intermediate 3 to obtain an intermediate 4; step 5): coupling the intermediate 4 with amino-protected S-isoserine to obtain an intermediate 5; step 6): deprotection of intermediate 5 gives intermediate 6; step 7): and (4) deprotecting the intermediate 6 to obtain 3N-isepamicin.

Description

Synthetic method of 3N-isepamicin
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a synthetic method of 3N-isepamicin.
Background
Isepamicin sulfate is a semi-synthetic aminoglycoside antibiotic widely used clinically, and is mainly used for treating gram-negative bacterial infection.
The isepamicin sulfate can generate a plurality of byproducts and degradation products in the synthesis process, the generated related substances have reduced antibacterial activity and increased toxicity, and the clinical use effect is influenced, and 3N-isepamicin is found to be one of the main components of the isepamicin related substances through separation and identification.
In order to better control the quality of the isepamicin product, a large number of 3N-isepamicin controls are required, and the directed synthesis thereof is the best method.
Disclosure of Invention
It is an object of the present invention to provide a method for the synthesis of 3N-isepamicin which solves one or more of the above mentioned problems of the prior art.
The invention provides a synthetic method of 3N-isepamicin, which comprises the following steps:
step 1): the gentamicin B-end chain amino protection obtains an intermediate 1, which specifically comprises the following steps: gentamicin B reacts with methanol and ethyl trifluoroacetate to obtain an intermediate 1, and the chemical reaction formula is as follows:
Figure BDA0002865651800000011
step 2): performing silanization protection on the intermediate 1 to obtain an intermediate 2, which specifically comprises the following steps: the intermediate 1 reacts with acetonitrile and trimethylchlorosilane to obtain an intermediate 2, and the chemical reaction formula is as follows:
Figure BDA0002865651800000021
step 3): protecting the amino group of the intermediate 2 to obtain an intermediate 3, which specifically comprises the following steps: reacting the intermediate 2 with dichloromethane and Boc anhydride to obtain an intermediate 3, wherein the chemical reaction formula is shown as follows:
Figure BDA0002865651800000022
step 4): the intermediate 3 is subjected to desilication protection to obtain an intermediate 4, which specifically comprises the following steps: adding the intermediate 3 into water, adjusting the pH value by hydrochloric acid, adding ethanol to react to obtain an intermediate 4, wherein the chemical reaction formula is as follows:
Figure BDA0002865651800000023
step 5): coupling the intermediate 4 with amino-protected S-isoserine to obtain an intermediate 5, which specifically comprises the following steps: dissolving the intermediate 4 in acetone, adding DCC and DMAP under an ice bath condition, and continuously adding N-substituted phthalic anhydride- (S) -isoserine to participate in a reaction to obtain an intermediate 5, wherein the chemical reaction formula is as follows:
Figure BDA0002865651800000024
step 6): and (3) deprotecting the intermediate 5 to obtain an intermediate 6, which specifically comprises: intermediate 5 was dissolved in absolute ethanol and the pH was adjusted by HCl and by concentrated ammonia to give intermediate 6, the chemical reaction formula is shown below:
Figure BDA0002865651800000031
step 7): and (3) carrying out deprotection on the intermediate 6 to obtain 3N-isepamicin, which specifically comprises the following steps: the intermediate 6 reacts with water and hydrazine hydrate to obtain 3N-isepamicin, and the chemical reaction formula is as follows:
Figure BDA0002865651800000032
in certain embodiments, the specific steps of step 1) are:
dissolving gentamicin B in methanol, magnetically stirring for 10min, adding ethyl trifluoroacetate, heating in a water bath at 80 ℃ to reflux, keeping the temperature for reaction for 5h, naturally cooling, and concentrating the reaction solution under reduced pressure to obtain an intermediate 1.
In certain embodiments, the specific steps of step 2) are:
dissolving the intermediate 1 in acetonitrile, adding trimethylchlorosilane, heating in a water bath to 70-75 ℃, carrying out reflux reaction for 4 hours until the reaction liquid is clear, and carrying out reduced pressure concentration on the reaction liquid to obtain an intermediate 2.
In certain embodiments, the specific steps of step 3) are:
intermediate 2 and dichloromethane were added to a three-necked flask, magnetically stirred, Boc anhydride was further added, reacted at room temperature overnight, and dichloromethane was removed under reduced pressure to give intermediate 3.
In certain embodiments, the specific steps of step 4) are:
dissolving the intermediate 3 in water, adjusting the pH value by hydrochloric acid, stirring and reacting at room temperature for 1h until the intermediate 3 is completely dissolved in water, adding ethanol, continuously stirring for 30min, when a solid is precipitated, performing ice bath overnight, performing suction filtration, and drying a filter cake to obtain an intermediate 4.
In certain embodiments, the specific steps of step 5) are:
dissolving the intermediate 4 in acetone, starting stirring, adding DCC and DMAP under an ice-bath condition, stirring for 10min, continuously adding N-substituted phthalic anhydride- (S) -isoserine, reacting for 6h under the condition of heat preservation, concentrating under reduced pressure until the residue is dry, and recrystallizing the residue by using a mixture of acetonitrile and water to obtain an intermediate 5.
In certain embodiments, the specific steps of step 6) are:
dissolving the intermediate 5 in absolute ethyl alcohol, introducing HCl under magnetic stirring to saturation, continuously reacting at room temperature for 4 hours, adjusting the pH to 8-10 by using concentrated ammonia water, continuously stirring for 1 hour, concentrating under reduced pressure, extracting the residue by using methanol, and concentrating to dryness to obtain an intermediate 6.
In certain embodiments, the specific steps of step 7) are:
and adding the intermediate 6 into a reaction bottle, adding water and hydrazine hydrate under magnetic stirring, reacting for 2 hours at room temperature, concentrating, performing ion exchange column chromatography on residues, and freeze-drying a product to obtain the 3N-isepamicin.
In certain embodiments, the pH is adjusted to 2 to 3 by hydrochloric acid.
In certain embodiments, the pH is adjusted to 8 to 10 by ammonia.
In certain embodiments, the protecting agent used in step 1) is ethyl trifluoroacetate.
In certain embodiments, the silylation protectant used in step 2) is trimethylchlorosilane or hexamethyldisilazane.
In certain embodiments, the silylation protectant used in step 2) is trimethylchlorosilane.
In certain embodiments, the protecting agent used in step 3) is Boc anhydride.
In certain embodiments, the deprotection of step 4) is performed under acidic to neutral conditions.
In certain embodiments, the protecting agent for amino-protected S-isoserine of step 5) is phthalic anhydride.
In certain embodiments, step 6) deprotection is first Boc-removed with hydrochloric acid and then neutralized with ammonia to basic trifluoroacetyl group.
Has the advantages that: the synthetic method of the 3N-isepamicin has low synthetic cost and higher product purity and yield, and can better perform oriented synthesis. Because a large amount of 3N-isepamicin reference substances are needed in the process of controlling the quality of the isepamicin product, the synthesis method provided by the invention can better control the quality of the isepamicin product.
Detailed Description
The present invention will be described in further detail below with reference to embodiments.
The method for synthesizing the 3N-isepamicin is characterized by comprising the following steps:
step 1): the gentamicin B-end chain amino protection obtains an intermediate 1, which specifically comprises the following steps:
dissolving 25g of gentamicin B in 300ml of methanol, magnetically stirring for 10min, adding 8.4g of ethyl trifluoroacetate, heating in a water bath until reflux, carrying out heat preservation reaction for 5h, naturally cooling, then concentrating the reaction solution under reduced pressure, and directly using the residue for the next reaction without treatment.
The chemical reaction formula is shown as follows:
Figure BDA0002865651800000051
step 2): performing silanization protection on the intermediate 1 to obtain an intermediate 2, which specifically comprises the following steps:
dissolving the intermediate 1 obtained in the previous step in 180ml of acetonitrile, adding 60ml of trimethylchlorosilane, heating in a water bath to 70-75 ℃, carrying out reflux reaction for 4h until the reaction solution is clear, concentrating the reaction solution under reduced pressure, and directly using the residue for the next step without treatment.
The chemical reaction formula is shown as follows:
Figure BDA0002865651800000052
step 3): protecting the amino group of the intermediate 2 to obtain an intermediate 3, which specifically comprises the following steps:
the intermediate 2 obtained in the above reaction and 80ml of dichloromethane were charged into a 100ml three-necked flask, magnetically stirred, and 42g of Boc anhydride was further added thereto, reacted at room temperature overnight, and dichloromethane was removed under reduced pressure, and the residue was used in the next reaction without further treatment.
The chemical reaction formula is shown as follows:
Figure BDA0002865651800000061
step 4): the intermediate 3 is subjected to desilication protection to obtain an intermediate 4, which specifically comprises the following steps:
adding 50ml of water into the intermediate 3 obtained in the previous step, adjusting the pH value to 2-3 with 6N hydrochloric acid, stirring at room temperature for reaction for 1h until the intermediate is completely dissolved, adding 1ml of ethanol, continuing stirring for 30min, separating out white solid, carrying out ice bath overnight, carrying out suction filtration, drying a filter cake to obtain 30.1g of intermediate 4, MS [ M +1 ]]+＝779.6
The chemical reaction formula is shown as follows:
Figure BDA0002865651800000062
step 5): coupling the intermediate 4 with amino-protected S-isoserine to obtain an intermediate 5, which specifically comprises the following steps:
dissolving 20g of intermediate 4 in 150ml of acetone, starting stirring, adding DCC2g and 0.1g of DMAP under the ice-bath condition, stirring for 10min, and continuously adding N-substituted phthalic anhydride- (S) -iso-isomerSerine 8.2g, reaction for 6h under constant temperature, vacuum concentration to dryness, and recrystallizing the residue with acetonitrile/water (2/1) to obtain white solid granule 15.2g, MS [ M +1 ]]+＝996.6。
The chemical reaction formula is shown as follows:
Figure BDA0002865651800000063
step 6): and (3) deprotecting the intermediate 5 to obtain an intermediate 6, which specifically comprises:
dissolving 15.2g of the intermediate 5 in 50ml of absolute ethyl alcohol, magnetically stirring, introducing HCl until saturation, continuously reacting at room temperature for 4 hours until the pH value of concentrated ammonia water is 8-10, stirring for 1 hour, concentrating under reduced pressure, extracting residue with methanol, concentrating to dryness, and directly using for the next reaction.
The chemical reaction formula is shown as follows:
Figure BDA0002865651800000071
step 7): and (3) carrying out deprotection on the intermediate 6 to obtain 3N-isepamicin, which specifically comprises the following steps:
adding the intermediate 6 obtained in the previous step into a 100ml reaction bottle, adding 20ml water and 3g hydrazine hydrate into the reaction bottle by magnetic stirring, reacting for 2h at room temperature, concentrating, performing ion exchange column chromatography on the residue (HD-2 resin, eluting with 0.1N ammonia water), and lyophilizing to obtain white solid 5.8g, MS [ M +1 ]]+＝570.4。
The chemical reaction formula is shown as follows:
Figure BDA0002865651800000072
in conclusion, the synthesis method of the 3N-isepamicin has low synthesis cost, high product purity and yield and can better perform oriented synthesis. Because a large amount of 3N-isepamicin reference substances are needed in the process of controlling the quality of the isepamicin product, the synthesis method provided by the invention can better control the quality of the isepamicin product.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these should be considered as within the scope of the present invention.

Claims (10)

  1. The synthesis method of the 1.3N-isepamicin is characterized by comprising the following steps:
    step 1): the gentamicin B-end chain amino protection obtains an intermediate 1, which specifically comprises the following steps: gentamicin B reacts with methanol and ethyl trifluoroacetate to obtain an intermediate 1, and the chemical reaction formula is as follows:
    Figure FDA0002865651790000011
    step 2): performing silanization protection on the intermediate 1 to obtain an intermediate 2, which specifically comprises the following steps: the intermediate 1 reacts with acetonitrile and trimethylchlorosilane to obtain an intermediate 2, and the chemical reaction formula is as follows:
    Figure FDA0002865651790000012
    step 3): protecting the amino group of the intermediate 2 to obtain an intermediate 3, which specifically comprises the following steps: reacting the intermediate 2 with dichloromethane and Boc anhydride to obtain an intermediate 3, wherein the chemical reaction formula is shown as follows:
    Figure FDA0002865651790000013
    step 4): the intermediate 3 is subjected to desilication protection to obtain an intermediate 4, which specifically comprises the following steps: adding the intermediate 3 into water, adjusting the pH value by hydrochloric acid, adding ethanol to react to obtain an intermediate 4, wherein the chemical reaction formula is as follows:
    Figure FDA0002865651790000014
    step 5): coupling the intermediate 4 with amino-protected S-isoserine to obtain an intermediate 5, which specifically comprises the following steps: dissolving the intermediate 4 in acetone, adding DCC and DMAP under an ice bath condition, and continuously adding N-substituted phthalic anhydride- (S) -isoserine to participate in a reaction to obtain an intermediate 5, wherein the chemical reaction formula is as follows:
    Figure FDA0002865651790000021
    step 6): and (3) deprotecting the intermediate 5 to obtain an intermediate 6, which specifically comprises: intermediate 5 was dissolved in absolute ethanol and the pH was adjusted by HCl and by concentrated ammonia to give intermediate 6, the chemical reaction formula is shown below:
    Figure FDA0002865651790000022
    step 7): and (3) carrying out deprotection on the intermediate 6 to obtain 3N-isepamicin, which specifically comprises the following steps: the intermediate 6 reacts with water and hydrazine hydrate to obtain 3N-isepamicin, and the chemical reaction formula is as follows:
    Figure FDA0002865651790000023
  2. 2. the method for synthesizing 3N-isepamicin according to claim 1, wherein the specific steps of step 1) are as follows:
    dissolving gentamicin B in methanol, magnetically stirring for 10min, adding ethyl trifluoroacetate, heating in a water bath at 80 ℃ to reflux, keeping the temperature for reaction for 5h, naturally cooling, and concentrating the reaction solution under reduced pressure to obtain an intermediate 1.
  3. 3. The method for synthesizing 3N-isepamicin according to claim 1, wherein the specific steps of step 2) are as follows:
    dissolving the intermediate 1 in acetonitrile, adding trimethylchlorosilane, heating in a water bath to 70-75 ℃, carrying out reflux reaction for 4 hours until the reaction liquid is clear, and carrying out reduced pressure concentration on the reaction liquid to obtain an intermediate 2.
  4. 4. The method for synthesizing 3N-isepamicin according to claim 1, wherein the specific steps of step 3) are as follows:
    intermediate 2 and dichloromethane were added to a three-necked flask, magnetically stirred, Boc anhydride was further added, reacted at room temperature overnight, and dichloromethane was removed under reduced pressure to give intermediate 3.
  5. 5. The method for synthesizing 3N-isepamicin according to claim 1, wherein the specific steps of step 4) are as follows:
    dissolving the intermediate 3 in water, adjusting the pH value by hydrochloric acid, stirring and reacting at room temperature for 1h until the intermediate 3 is completely dissolved in water, adding ethanol, continuously stirring for 30min, when a solid is precipitated, performing ice bath overnight, performing suction filtration, and drying a filter cake to obtain an intermediate 4.
  6. 6. The method for synthesizing 3N-isepamicin according to claim 1, wherein the specific steps of step 5) are as follows:
    dissolving the intermediate 4 in acetone, starting stirring, adding DCC and DMAP under an ice-bath condition, stirring for 10min, continuously adding N-substituted phthalic anhydride- (S) -isoserine, reacting for 6h under the condition of heat preservation, concentrating under reduced pressure until the mixture is dry, and recrystallizing residues by using a mixture of acetonitrile and water (the volume ratio is 2/1) to obtain an intermediate 5.
  7. 7. The method for synthesizing 3N-isepamicin according to claim 1, wherein the specific steps of step 6) are as follows:
    dissolving the intermediate 5 in absolute ethyl alcohol, introducing HCl under magnetic stirring to saturation, continuously reacting at room temperature for 4 hours, adjusting the pH to 8-10 by using concentrated ammonia water, continuously stirring for 1 hour, concentrating under reduced pressure, extracting the residue by using methanol, and concentrating to dryness to obtain an intermediate 6.
  8. 8. The method for synthesizing 3N-isepamicin according to claim 1, wherein the specific steps of step 7) are as follows:
    and adding the intermediate 6 into a reaction bottle, adding water and hydrazine hydrate under magnetic stirring, reacting for 2 hours at room temperature, concentrating, performing ion exchange column chromatography on residues, and freeze-drying a product to obtain the 3N-isepamicin.
  9. 9. The method of synthesizing 3N-isepamicin according to claim 5, wherein the pH is adjusted to 2 to 3 by hydrochloric acid.
  10. 10. The method of synthesizing 3N-isepamicin according to claim 7, wherein the pH is adjusted to 8 to 10 by ammonia.
CN202011583251.9A 2020-12-28 2020-12-28 Synthetic method of 3N-isepamicin Pending CN112645995A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011583251.9A CN112645995A (en) 2020-12-28 2020-12-28 Synthetic method of 3N-isepamicin

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011583251.9A CN112645995A (en) 2020-12-28 2020-12-28 Synthetic method of 3N-isepamicin

Publications (1)

Publication Number Publication Date
CN112645995A true CN112645995A (en) 2021-04-13

Family

ID=75363810

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011583251.9A Pending CN112645995A (en) 2020-12-28 2020-12-28 Synthetic method of 3N-isepamicin

Country Status (1)

Country Link
CN (1) CN112645995A (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20040025060A (en) * 2002-09-18 2004-03-24 정용진 The preparation process of isepamicin
CN101469007A (en) * 2007-12-29 2009-07-01 北京琥珀光华医药科技开发有限公司 Novel technique for synthesizing isepamicin sulfate
CN102093444A (en) * 2011-01-10 2011-06-15 江西制药有限责任公司 Method for preparing isepamicin and salts thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20040025060A (en) * 2002-09-18 2004-03-24 정용진 The preparation process of isepamicin
CN101469007A (en) * 2007-12-29 2009-07-01 北京琥珀光华医药科技开发有限公司 Novel technique for synthesizing isepamicin sulfate
CN102093444A (en) * 2011-01-10 2011-06-15 江西制药有限责任公司 Method for preparing isepamicin and salts thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
R. VOGEL，等: "Determination of isepamicin sulfate and related compounds by high performance liquid chromatography using evaporative light scattering detection", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 *
王建，等: "硫酸异帕米星中有关物质的分离、鉴定和抗菌活性研究", 《中国药学杂质》 *

Similar Documents

Publication Publication Date Title
CN105461632B (en) A kind of preparation method of N acetyl L carnosines
CN107602661B (en) Preparation method of polaprezinc
KR20130062913A (en) Crystalline oxidized glutathione and production method therefor
CN108299322B (en) Method for preparing gadobutrol
CN108003105B (en) Method for synthesizing micromolecular amino acid derivative ectoin
CN112645995A (en) Synthetic method of 3N-isepamicin
CN112679567B (en) Synthesis method of 1N, 3N-isepamicin
EP3464237A1 (en) Novel process for the preparation of gadolinium complex of (4s)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9- triazaundecanedioic acid disodium (gadoxetate disodium)
CN111646998A (en) Synthesis method of ibrutinib
US5618936A (en) Process for preparing (S) (+)-4,4'-(1-methyl-1,2-ethanediyl)-bis (2,6-piperazinedione)
WO2005090306A1 (en) Process for the purification of tryptophan
CN109467592A (en) A kind of preparation method of Dalbavancin
CN111051289A (en) Protected L-carnosine derivative, L-carnosine and method for producing crystalline L-carnosine zinc complex
EP3864004B1 (en) Process for the synthesis of carglumic acid
CN114436930A (en) Synthesis method of Boc-L-hydroxyproline
CN111116694B (en) P1，P4Process for the preparation of di (uridine 5' -) tetraphosphate
CN114369129A (en) Synthetic method of chlorinated nicotinamide ribose
CN110878108B (en) Synthetic method of prazazolmitrin
CN108948157B (en) Method for preparing telavancin
CN113563401A (en) Novel cordycepin alkanamide derivative and preparation method and application thereof
CN111393493B (en) Synthetic method of tildipirosin
EP0665229A1 (en) Process for the production of nucleic acid base derivatives
CN109021019B (en) Preparation method of miriplatin
CN109096148B (en) Method for preparing vorinostat by using modified mesoporous material through one-pot method
CN111925298B (en) 4-CNAB and preparation method thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
CB02 Change of applicant information
CB02 Change of applicant information

Address after: 219 Furong Zhongsi Road, Xishan Economic and Technological Development Zone, Wuxi City, Jiangsu Province, 214000

Applicant after: Zhuohe Pharmaceutical Group Co.,Ltd.

Address before: 219 Furong Zhongsi Road, Xishan Economic and Technological Development Zone, Wuxi City, Jiangsu Province, 214000

Applicant before: Zhuohe Pharmaceutical Group Co.,Ltd.

RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20210413