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Preparation method of rosuvastatin calcium intermediate

A compound, the technology of isopropyl, applied in the field of drug synthesis, can solve the problems that the synthesis process is not suitable for industrialization, there is no commercial supplier, and the yield of the synthesis process product is low, so as to avoid unstable brominated intermediates , suitable for large-scale production, high product yield

Inactive Publication Date: 2019-05-31
SHANGYU JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] But the product yield of this synthesis process is low, and there is no commercial supplier of raw material triphenylphosphonium hydrobromide or triphenylphosphonium fluoroborate, so this synthesis process is not suitable for industrialization

Method used

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  • Preparation method of rosuvastatin calcium intermediate
  • Preparation method of rosuvastatin calcium intermediate
  • Preparation method of rosuvastatin calcium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 3.5g of 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-methanol (compound I), 2.6g tris Phenylphosphine and 30ml of toluene were added to a 100ml three-necked flask, and 1.84g of 48% hydrobromic acid was added, heated to reflux and stirred. After the reaction was completed, it was cooled and crystallized, and dried to obtain a white solid, which was [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonamido)-5- Pyrimidinyl]triphenylphosphine bromide (compound II). Yield: 85%; Purity: 99.0%.

[0032] 1 H NMR (400MHz, DMSO-d6): δ7.87(m, 3H), 7.63(m, 6H), 7.27(m, 8H), 7.13(t, J=8.4Hz, 2H), 5.08(d, J =13.6Hz,2H),3.49(s,3H),3.40(s,3H),2.86(m,1H),0.79(d,J=4.4Hz,6H)

Embodiment 2

[0034] 3.5g of 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-methanol (compound I), 2.6g tris Phenylphosphine and 30ml of acetonitrile were added to a 100ml three-necked flask, and 1.84g of 48% hydrobromic acid was added, heated to reflux and stirred. After the reaction was completed, it was concentrated to dryness to obtain a white solid, which was [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonamido)-5-pyrimidinyl ] Triphenylphosphine bromide (compound II). Yield: 98%; Purity: 96.0%.

Embodiment 3-10

[0036] According to the method shown in Example 1, Compound II was prepared by adjusting the ratio between Compound I, hydrogen bromide and triphenylphosphine in hydrobromic acid and the type of solvent. The results are shown in Table 1.

[0037] Preparation of Table 1 Compound II

[0038]

[0039] As can be seen from Table 1, considering the comprehensive factors of the yield and purity of compound II, the experimental results of acetonitrile or acetonitrile / water mixed solvent as solvent are better than dichloromethane and tetrahydrofuran.

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Abstract

The invention relates to a preparation method of a rosuvastatin calcium intermediate [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonamide)-5-pyrimidyl]triphenyl phosphonium bromide. The preparation method includes following steps: enabling 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-methanol, hydrobromic acid and triphenylphosphine to react in an organic solvent to obtain a target compound. The preparation method is easy-to-obtain in raw material, simple in operation and high in yield, phosphorus-containing wastewater and phosphorus-containing waste residue are reduced effectively, production cost is lowered, and large-scale production is facilitated.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, in particular to a preparation of rosuvastatin calcium intermediate [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonamide) )-5-pyrimidinyl]triphenylphosphine bromide method. Background technique [0002] Rosuvastatin Calcium (Rosuvastatin Calcium) is a statin blood lipid regulating drug developed by Shionogi Company in Japan. It belongs to HMG-CoA reductase inhibitors and can reduce elevated low-density cholesterol, total cholesterol, triglyceride Ester and apoprotein B concentration, while increasing the concentration of high-density cholesterol. It can be used for the comprehensive treatment of primary hypercholesterolemia, mixed lipodystrophy and homozygous familial hypercholesterolemia, and is called a super statin. An important intermediate for the synthesis of rosuvastatin calcium is [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanol) shown in the following formula I...

Claims

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Application Information

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IPC IPC(8): C07F9/6512
Inventor 邱卓汪博宇
Owner SHANGYU JINGXIN PHARMA
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